Archive for the ‘Bone Marrow Stem Cells’ Category

As a hematologist-oncologist in Miami, Mikkael Sekeres always hopes his patients will find a perfect match for the bone marrow transplant they need to save their lives but he doesnt expect it. Most of his patients are Latino or African American, and rates of perfect matches are much lower for racial or ethnic minorities.

That gloomy picture could soon change. A study published Wednesday in the Journal of Clinical Oncology found that certain unmatched donors, or people whose bone marrow does not as closely resemble that of the patients, provided similar outcomes to matched donors so long as patients receive a key drug called cyclophosphamide to prevent dangerous complications. That suggests that patients who need a transplant might be able to safely consider both matched and some unmatched donors, vastly expanding the pool of potential acceptable donors for all patients, though particularly those of African, Latino, or Asian ancestry.

Its much harder to find a match for most of my patients. Looking to people who are donor unrelated and arent a perfect match for my patients has become the norm, said Sekeres, who is the chief of hematology at Sylvester Cancer Center at the University of Miami and did not work on the study. Thats why this study really resonated with me. The classic teaching is you want a perfect match as opposed to less than perfect. What this study suggests is, if you use the right drugs after transplant, it may not be as big of a deal.

If so, up to roughly 84% of African American patients might have a potential donor in the national registry. Currently, less than 30% of African American patients have a potential match in the NMDP registry, previously called the National Marrow Donor Program.

Bone marrow transplants, also called hematopoietic cell or blood stem cell transplants, are essentially immune system transplants, and often represent a patients last chance for a cure for blood cancers like leukemia and lymphoma. Oncologists give chemotherapy first to put the cancer in remission, but the chemotherapy also does substantial damage to healthy bone marrow, where stem cells that give rise to blood and immune cells reside. The transplanted immune system would then replenish the lost stem cells as well as attack any remaining cancer in the patient.

The trouble is that the grafted immune system can also reject its new home, attacking healthy tissues in a potentially fatal complication known as graft versus host disease. Your native immune system avoids this by using a system of proteins called HLAs or human leukocyte antigens. Every cell carries these proteins like a security badge, identifying itself as part of your own body to patrolling immune cells. A matched donor would thus carry the same eight major HLA markers as the recipient or be an eight of eight match to make it more likely the transplanted immune system will settle into the new host without much fuss.

For many years, it was known having a donor whose immune system is matched to yours conferred a better outcome. Back when I was a fellow, outcomes were dismal when patients got an unmatched donor, said Brian Shaffer, a bone marrow transplant physician at Memorial Sloan Kettering Cancer Center and the lead author on the study.

Then, several years ago, scientists at Johns Hopkins University showed that cyclophosphamide could lower the risk of these complications for half-matched first-degree relative donors. Blood stem cells are resistant to this particular chemotherapy, but not so much immune cells like T and B cells that drive graft versus host disease. These immune cells are particularly vulnerable to the toxin if theyre activated and in the process of proliferating, Shaffer said.

That means when the transplanted immune system goes into the patient, some of these T and B cells will recognize theyre in the wrong body and begin lashing out against the recipient, but make themselves more vulnerable to cyclophosphamide in doing so. That means the drug can selectively delete the immune cells that are most likely to cause dangerous complications.

Other T cells will remain quiet, because theyre happy with the host, Shaffer said. These angry T cells will go into cell division, and theyre more exposed to cyclophosphamide.

Some of the first indications that this strategy would work to ease even unrelated and unmatched immune systems into patients came in 2021. A team of researchers saw favorable outcomes in the overall survival of about 80 patients who received either an unmatched unrelated transplant after one year. This study expands those findings with data collected from approximately 10,000 patients treated for acute leukemia or myelodysplastic syndromes.

The study was possible partly because so many patients, particularly those with non-European ancestry, cannot find an 8/8 match in the registry. So, their only option is to go down to a 7/8 or lower mismatched donor. Some centers were already using cyclophosphamide to prevent graft versus host disease, though others use another drug called a calcineurin inhibitor. Shaffer and his colleagues used data from 153 centers comparing patients who received either an 8/8 or 7/8 match and either cyclophosphamide or a calcineurin inhibitor.

The major finding is that the patients who had post-transplant cyclophosphamide had no differences in survival or any other sort of key clinical outcome, freedom from graft versus host disease and other complications, from matched or mismatched donors, Shaffer said. That wasnt true for the patients who received calcineurin inhibitors. These patients also had worse survival, relapse occurrence, and graft versus host disease compared to those who received cyclophosphamide.

I was pleased to read this article, said Warren Fingrut, a transplant and cell therapy physician and MD Anderson Cancer Center who did not work on the study. Allowing seven of eight mismatched unrelated donors will extend access to many more patients, especially those from racial, ethnic minority groups to receive transplantation.

While the study was specifically on patients with acute leukemia or myelodysplastic syndromes, the findings are of great interest for patients who have other hematologic malignancies and nonmalignant conditions who also receive transplants, Fingrut said. Though, he added, it may still be important to replicate the work in other indications.

According to the analysis, broadening the pool of bone marrow donors to include 7/8 mismatched transplants increases the potential match rate for Asians and Hispanics from less than 50% to close to 90%. The potential match rate for African Americans rises to 84%. The potential match rate for white Americans also goes up from about 79% to 99%.

Those are enormous gains and would likely help substantially in reducing health disparities in these cancers, Fingrut said, though it wouldnt solve all the disparities in transplant access. One problem is even if a potential donor exists in the registry for a patient, many of these donors cannot actually donate. That might be because their contact information changed and arent reachable, they have new health conditions that preclude them from donating, or they may no longer be interested.

About half of donors are unavailable overall for confirmatory typing. When you zoom in on African ancestry, its less than one third that are available, Fingrut said. Thats not improving over time, and its not just due to the Covid-19 pandemic.

This study opens an avenue to getting around that problem, Fingrut said. Transplant doctors could consider 7/8 unmatched donors alongside matched donors for patients who have worse chances of finding a match in the registry. If you go after the few unrelated donors that never show up, and only then you switch to mismatched donors or alternatives like cord blood donors, it in fact impacts overall survival, Fingrut said. These patients cannot wait months and months for a donor that never materializes.

Dropping down to a four, five, or six out of eight match would further increase the match rate to nearly 100% for all patients, although its still unclear if using more heavily mismatched donors would worsen outcomes. Everyone is eagerly awaiting that data, Fingrut said.

But there is also another way to improve the match rate without resorting to more heavily mismatched donors, he pointed out. More people could join the donor registry.

An earlier version of this article incorrectly described a 2021 study. Participants in that trial received only unmatched, unrelated transplants.

The rest is here:
Bone marrow donors neednt be perfect match, study says, paving way for more equitable access - STAT

A seventh person has essentially been cured of HIV after receiving a stem cell transplant nearly a decade ago, doctors announced Thursday.

The 60-year-old unidentified German man was suffering from acute myeloid leukemia when he underwent the risky procedure to replace his unhealthy bone marrow in October 2015.

He quit taking anti-retroviral drugs which stop HIV from reproducing in September 2018. He remains in viral remission and appears to be cancer-free.

A healthy person has many wishes, a sick person only one, the man, who wishes to remain anonymous, said of his progress.

Dr. Christian Gaebler, a physician-scientist at the Charit-Universittsmedizin Berlin, is slated to present the case next week at the 25thInternational AIDS Conference.

The longer we see these HIV remissions without any HIV therapy, the more confidence we can get that were probably seeing a case where we really have eradicated all competent HIV, Gaebler said.

At a news conference last week, International AIDS Society President Sharon Lewin cautioned against using the word cure.

Still, she said, being in remission for more than five years means he would be close to being considered cured.

There is one major difference between the German mans case and most of the rest.

Five of the other six patients received stem cells from donors with two copies of a rare genetic mutation that stops HIV from replicating.

The German patient is said to be the first to have received stem cells from a donor with just one copy of the mutated gene and he had a copy of the gene himself.

About1% of Caucasians have two copies of thedefective gene, while 10% to 18% of people with European heritage are estimated to have one copy of the gene, thus expanding the potential donor pool.

Some 39 million people around the world are living with HIV, the virus that causes AIDS. Very few will be able to access this treatment, as it is reserved for those with HIV and aggressive leukemia.

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Excerpt from:
7th person likely cured of HIV in a remarkable case - New York Post

Copelan EA, Chojecki A, Lazarus HM, Avalos BR. Allogeneic hematopoietic cell transplantation; the current renaissance. Blood Rev. 2019;34:3444.

Article CAS PubMed Google Scholar

Modi D, Uberti J. Hematopoietic stem cell transplantation: an overview. In: Pulmonary and Critical Care Considerations of Hematopoietic Stem Cell Transplantation. Springer International Publishing: Cham, 2023,115.

Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, et al. One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2:e91e100.

Article PubMed Google Scholar

Wong E, Davis JE, Grigg A, Szer J, Ritchie D. Strategies to enhance the graft versus tumour effect after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transpl. 2019;54:17589.

Article CAS Google Scholar

Conway EM. Reincarnation of ancient links between coagulation and complement. J Thromb Haemost. 2015;13:S121S132.

Article CAS PubMed Google Scholar

Ricklin D, Reis ES, Lambris JD. Complement in disease: a defence system turning offensive. Nat Rev Nephrol. 2016;12:383401.

Article CAS PubMed PubMed Central Google Scholar

Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD. Interactions between coagulation and complement-their role in inflammation. Semin Immunopathol. 2012;34:15165.

Article CAS PubMed Google Scholar

Duval A, Frmeaux-Bacchi V. Complement biology for hematologists. Am J Hematol 2023;98. https://doi.org/10.1002/ajh.26855.

Schmidt CQ, Schrezenmeier H, Kavanagh D. Complement and the prothrombotic state. Blood. 2022;139:195472.

Article CAS PubMed Google Scholar

Milone G, Bellofiore C, Leotta S, Milone GA, Cupri A, Duminuco A, et al. Endothelial dysfunction after hematopoietic stem cell transplantation: a review based on physiopathology. J Clin Med. 2022;11:623.

Article CAS PubMed PubMed Central Google Scholar

Moreno-Castao AB, Salas MQ, Palomo M, Martinez-Sanchez J, Rovira M, Fernndez-Avils F et al. Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development. Front Immunol 2022;13. https://doi.org/10.3389/fimmu.2022.1050994.

Stassen J, Arnout J, Deckmyn H. The hemostatic system. Curr Med Chem. 2004;11:224560.

Article CAS PubMed Google Scholar

Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemost. 2001;85:95865.

Article CAS PubMed Google Scholar

Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I molecular mechanisms of activation and regulation. Front Immunol 2015; 6. https://doi.org/10.3389/fimmu.2015.00262.

Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: Role in immunity. Front Immunol 2015;6. https://doi.org/10.3389/fimmu.2015.00257.

Mastellos DC, Hajishengallis G, Lambris JD. A guide to complement biology, pathology and therapeutic opportunity. Nat Rev Immunol. 2024;24:11841.

Article CAS PubMed Google Scholar

Elvington M, Liszewski MK, Atkinson JP. Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol Rev. 2016;274:915.

Article CAS PubMed PubMed Central Google Scholar

Noris M, Galbusera M. The complement alternative pathway and hemostasis. Immunol Rev. 2023;313:13961.

Article CAS PubMed Google Scholar

Donat C, Klm R, Csorba K, Tuncer E, Tsakiris DA, Trendelenburg M. Complement C1q enhances primary hemostasis. Front Immunol 2020;11. https://doi.org/10.3389/fimmu.2020.01522.

Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F, et al. Interaction between the coagulation and complement system. Adv Exp Med Biol. 2008;632:719.

CAS PubMed PubMed Central Google Scholar

del Conde I, Crz MA, Zhang H, Lpez JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system. J Exp Med. 2005;201:8719.

Article PubMed PubMed Central Google Scholar

Eriksson O, Mohlin C, Nilsson B, Ekdahl KN. The human platelet as an innate immune cell: interactions between activated platelets and the complement system. Front Immunol 2019;10. https://doi.org/10.3389/fimmu.2019.01590.

Arbesu I, Bucsaiova M, Fischer MB, Mannhalter C. Platelet-borne complement proteins and their role in plateletbacteria interactions. J Thromb Haemost. 2016;14:224152.

Article CAS PubMed PubMed Central Google Scholar

Puy C, Pang J, Reitsma SE, Lorentz CU, Tucker EI, Gailani D, et al. Cross-talk between the complement pathway and the contact activation system of coagulation: activated factor XI neutralizes complement factor H. J Immunol. 2021;206:178492.

Article CAS PubMed Google Scholar

Endo Y, Matsushita M, Fujita T. New insights into the role of ficolins in the lectin pathway of innate immunity. Int Rev Cell Mol Biol. 2015;316:49110.

Article CAS PubMed Google Scholar

de Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: a triangular relationship. Cell Mol Immunol. 2019;16:1927.

Article PubMed Google Scholar

Zhu Y, Chen X, Liu X. NETosis and neutrophil extracellular Traps in COVID-19: immunothrombosis and beyond. Front Immunol. 2022;13. https://doi.org/10.3389/fimmu.2022.838011.

Lazana I. Transplant-associated thrombotic microangiopathy in the context of allogenic hematopoietic stem cell transplantation: where we stand. Int J Mol Sci. 2023;24:1159.

Article CAS PubMed PubMed Central Google Scholar

Meri S, Bunjes D, Cofiell R, Jodele S. The role of complement in HSCT-TMA: basic science to clinical practice. Adv Ther. 2022;39:3896915.

Article CAS PubMed PubMed Central Google Scholar

Gloude NJ, Khandelwal P, Luebbering N, Lounder DT, Jodele S, Alder MN, et al. Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD. Blood. 2017;130:125966.

Article CAS PubMed PubMed Central Google Scholar

Mohty M, Malard F, Alaskar AS, Aljurf M, Arat M, Bader P, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transpl. 2023;58:74954.

Article Google Scholar

Mavrikou I, Chatzidimitriou D, Skoura L, Nikolousis E, Sakellari I, Gavriilaki E. Molecular advances in sinusoidal obstruction syndrome/veno-occlusive disease. Int J Mol Sci. 2023;24. https://doi.org/10.3390/ijms24065620.

Socie G, Michonneau D. Milestones in acute GVHD pathophysiology. Front Immunol 2022;13. https://doi.org/10.3389/fimmu.2022.1079708.

Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377:256579.

Article CAS PubMed Google Scholar

Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121:498596.

Article CAS PubMed Google Scholar

Oliver M, Patriquin C. Paroxysmal nocturnal hemoglobinuria: current management, unmet needs, and recommendations. J Blood Med. 2023;14:61328.

Article CAS PubMed PubMed Central Google Scholar

Yerigeri K, Kadatane S, Mongan K, Boyer O, Burke LL, Sethi SK, et al. Atypical hemolytic-uremic syndrome: genetic basis, clinical manifestations, and a multidisciplinary approach to management. J Multidiscip Health. 2023;ume 16:223349.

Article Google Scholar

Spasiano A, Palazzetti D, Dimartino L, Bruno F, Baccaro R, Pesce F, et al. Underlying genetics of aHUS: which connection with outcome and treatment discontinuation? Int J Mol Sci. 2023;24:14496.

Article CAS PubMed PubMed Central Google Scholar

Noris M, Remuzzi G. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015. Am J Kidney Dis. 2015;66:35975.

Article PubMed PubMed Central Google Scholar

Noris M, Remuzzi G. Genetics of immune-mediated glomerular diseases: focus on complement. Semin Nephrol. 2017;37:44763.

Article CAS PubMed Google Scholar

Delvasto-Nuez L, Jongerius I, Zeerleder S. It takes two to thrombosis: hemolysis and complement. Blood Rev. 2021;50:100834.

Article PubMed Google Scholar

Jger U, Barcellini W, Broome CM, Gertz MA, Hill A, Hill QA, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648.

Article PubMed Google Scholar

Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol. 2022;44:34762.

Article CAS PubMed PubMed Central Google Scholar

Tsakiris DA, Tichelli A. Thrombotic complications after haematopoietic stem cell transplantation: early and late effects. Best Pr Res Clin Haematol. 2009;22:13745.

Article Google Scholar

Pihusch R, Salat C, Schmidt E. Ghring P, Pihusch M, Hiller E, et al. Hemostatic complications in bone marrow transplantation: a retrospective analysis of 447 patients. Transplantation. 2002;74:13039.

Article PubMed Google Scholar

Nadir Y, Brenner B. Hemorrhagic and thrombotic complications in bone marrow transplant recipients. Thromb Res. 2007;120:S92S98.

Article PubMed Google Scholar

Eftychidis I, Sakellari I, Anagnostopoulos A, Gavriilaki E. Endothelial dysfunction and vascular complications after allogeneic hematopoietic cell transplantation: an expert analysis. Expert Rev Hematol. 2021;14:83140.

Article CAS PubMed Google Scholar

Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, et al. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29:191204.

Article PubMed Google Scholar

Lia G, Giaccone L, Leone S, Bruno B. Biomarkers for early complications of endothelial origin after allogeneic hematopoietic stem cell transplantation: do they have a potential clinical role? Front Immunol. 2021;12. https://doi.org/10.3389/fimmu.2021.641427.

Chaturvedi S, Neff A, Nagler A, Savani U, Mohty M, Savani BN. Venous thromboembolism in hematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2016;51:4738.

Article CAS Google Scholar

Labrador J, Lopez-Anglada L, Perez-Lopez E, Lozano FS, Lopez-Corral L, Sanchez-Guijo FM, et al. Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients. Haematologica. 2013;98:43743.

Article PubMed PubMed Central Google Scholar

Lee A, Badgley C, Lo M, Banez MT, Graff L, Damon L, et al. Evaluation of venous thromboembolism prophylaxis protocol in hematopoietic cell transplant patients. Bone Marrow Transpl. 2023;58:124753.

Article Google Scholar

Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB. The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention. Blood. 2008;112:50410.

Article CAS PubMed Google Scholar

Gonsalves A, Carrier M, Wells PS, McDiarmid SA, Huebsch LB, Allan DS. Incidence of symptomatic venous thromboembolism following hematopoietic stem cell transplantation. J Thromb Haemost. 2008;6:146873.

Article CAS PubMed Google Scholar

Rotz SJ, Ryan TD, Hayek SS. Cardiovascular disease and its management in children and adults undergoing hematopoietic stem cell transplantation. J Thromb Thrombolysis. 2021;51:85469.

Article PubMed Google Scholar

Aghel N, Lui M, Wang V, Khalaf D, Mian H, Hillis C, et al. Cardiovascular events among recipients of hematopoietic stem cell transplantation-A systematic review and meta-analysis. Bone Marrow Transpl. 2023;58:47890.

See more here:
Hemostasis and complement in allogeneic hematopoietic stem cell transplantation: clinical significance of two interactive systems - Nature.com

Alexandra Gomez Arteaga, MD, hematologist/oncologist in the bone marrow transplant and cellular therapy program at Weill Cornell Medicine in New York, New York, discusses the rationale behind a retrospective study comparing Orca-T with posttransplant cyclophosphamide-based hematopoietic cell transplantation using data from existing studies that involved similar patient populations.

Arteaga also discusses the mechanism of action of Orca-T, a novel cell therapy under investigation. The agent works by leveraging regulatory T cells from allogeneic donors to control graft-vs-host disease (GVHD).

Transcription:

0:09 | Our field in allogeneic stem cell transplantation is changing, and we now have new ways of doing GVHD prophylaxis. The posttransplant cyclophosphamide studies and the platform have shown significant reduction in chronic GVHD. There might be other ways that we can improve outcomes by reducing other important things such as toxicities and relapse.

0:31 | Orca-T is a high precision immunotherapy that is a more organized fashion to create immune reconstitution. Based on the new changes in post transplant cyclophosphamide, we wanted to compare Orca-T [with] posttransplant cyclophosphamide since we currently are doing a study with Orca-T against the standard of care.

0:52 | With the current allografts, there are over 50 cell types that are infused together, and we have no control over how these cells interact for engraftment. Orca-T immune reconstitution, on the other hand, is the high-precision immunotherapy where the cells are in manufacture and divided into 3 main components. The first component is hematopoietic stem cells. The second component is highly purified T regulatory cells. The third component is the conventional cells.

1:20 | With this high precision immunotherapy, we can give the patient the exact number of cells at the exact time. On day 0, the patients get the stem cells from the T regulatory cells and these the regulatory cells are going to have an optimal immunomodulatory environment so that there's less GVHD. There is more organization of how the immune reconstitution happens.

Read this article:
Advancements in Stem Cell Transplantation: Comparing Orca-T With PTCy - Targeted Oncology

Study approval

All experiments were performed in accordance with protocols approved by the University of North Carolina Institutional Animal Care and Use Committee (application number 14-001). Prior to sample collection, all human patients signed informed consent under Duke University IRB study protocol Pro00110250. Healthy donor control cells were purchased from Memorial Blood Center (St. Paul, MN) where all commercially available products are collected with IRB approval or exemption.

C57BL/6 (strain 0000664) and C57BL/6JDBA/2 F1 (B6D2, strain 100006) mice were purchased from The Jackson Laboratory. The generation of enhanced GFP-expressing C57BL/6 mice has been described previously26. Donor and recipient mice were age-matched males between 8 and 16 weeks. Animals were housed under specific pathogen-free (SPF) conditions on a 12-h dark/light cycle at 2122C and 3070% humidity. Where applicable in all mouse studies, animals were euthanized via CO2-compressed carbon dioxide gas in cylinders followed by physical cervical dislocation to ensure death.

Eight- to 16-week-old B6 mice were given 0.4g recombinant mouse IL-17E/IL-25 (R&D Systems) by i.p. injection for 4 days. On day 5, cells were isolated from the mesenteric lymph nodes and peritoneum by peritoneal lavage using RPMI-1640 supplemented with 10% FBS, 2mM L-glutamine, 12mM HEPES, 0.1mM non-essential amino acids, 1mM sodium pyruvate, 1% Pen/Strep, and 50M 2-mercaptoethanol (complete media). ILC2s were isolated by negative selection with a MACS column using the following antibodies (anti-CD8 [clone 53-6.7], anti-CD4 [RM 4.4], anti-CD3 [clone 145-2C11], anti-TCR [UC7-13DS], anti-TER119 [TER-119], anti-B220 [RA3-6B2], anti-CD11b [M1/70], anti-NK1.1 [PK136], eBioscience; anti-CD11c [N418], anti-CD19 [MB19-1], anti-Ly6G [1A8], and anti-CD49b [DX5], BioLegend) and Streptavidin Microbeads (Miltenyi 130-048-101). Cells were expanded in culture at 2.25x105 cells/mL in 24 well flat bottom TC-treated plates or flasks (Corning) as described below.

ILC2s were cultured at 2.25x105 cells/mL for 6 days in complete media (RPMI-1640 supplemented with 10% FBS, 2mM L-glutamine, 12mM HEPES, 0.1mM non-essential amino acids, 1mM sodium pyruvate, 1% Pen/Strep, and 50M 2-mercaptoethanol) and supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech), with the media changed every 2 days. ILC2 activation was evaluated using flow cytometry on day 6 by surface and intracellular cytokine staining with antibodies against Lineage (eBioscience) and ST2 (Thermo Scientific). For experiments in which cells were generated via cytokine-mediated skewing (pcILC2s), cells were cultured at 2.25x105 cells/mL for 48h in complete media supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech). On Days 2 and 4, the media was replaced with complete R10 containing 10ng/ml rIL-7, 10ng/ml rIL-12, 10ng/ml rIL-1b, 10ng/ml rIL-15, 10ng/ml rIL-2, and 5ng/ml rIL-18.

Non-mobilized healthy donor peripheral blood (PB) leukapheresis products were purchased from Memorial Blood Center (St. Paul, MN), and human ILC2 cells were captured via the RosetteSep human ILC2 enrichment kit (STEMCELL Technologies), per the manufacturers instructions.

ILC2s were cultured at 2.25x105 cells/mL for 6 days in complete media (RPMI-1640 supplemented with 10% FBS, 2mM L-glutamine, 12mM HEPES, 0.1mM non-essential amino acids, 1mM sodium pyruvate, 1% Pen/Strep, and 50M 2-mercaptoethanol) and supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech), with the media changed every 2 days. ILC2 activation was evaluated using flow cytometry on day 6 by surface and intracellular cytokine staining with antibodies against Lineage (eBioscience) and ST2 (Thermo Scientific). For experiments in which cells were generated via cytokine-mediated skewing (pcILC2s), cells were cultured at 2.25x105 cells/mL for 48h in complete media supplemented with 10ng/ml rIL-7 and rIL-33 (PeproTech). On Days 2 and 4, the media was replaced with complete R10 containing 10ng/ml rIL-7, 10ng/ml rIL-12, 10ng/ml rIL-1b, 10ng/ml rIL-15, 10ng/ml rIL-2, and 5ng/ml rIL-18.

The phenotype and function of murine ILC2s were evaluated by flow cytometry with antibodies as listed in Supplementary Data2. Prior to transplantation T cells were evaluated by surface staining of CD4 (GK1.5) and CD8 (clone 53-6.7). Sample acquisition was performed using a BD LSRII or BD LSRFortessa (BD Bioscience) or a MACS Quant (Miltenyi Biotec), and data were analyzed by FlowJo v9/10 (TreeStar, BD) and Prism v10 (GraphPad).

Total T cells were isolated using a Cedarlane T cell recovery column kit (Cedarlane Laboratories), followed by antibody depletion using PE-conjugated anti-mouse B220 (RA3-B62) and anti-mouse CD25 (3C7) antibodies (eBioscience) and magnetic bead selection using anti-PE beads (130-0480801, Miltenyi Biotec). TCD bone marrow was prepared as described previously27. The day prior to transplantation, recipient mice received 950cGy of total body irradiation. Recipients were intravenously injected with 4106T cells and 3x106 TCD BM cells. For ILC2 treatment groups, B6D2 recipients also received 3 4x106 ILC2s, respectively. Recipients were monitored three times a week and scored for clinical GVHD symptoms (designated clinical score) using a semiquantitative scoring system as previously described28,29; animals were coded for these evaluations. The sample size was chosen for the effect size needed based on our previous experience with sample sizes needed to demonstrate a significant difference in GVHD scoring between control and treated groups. For the scoring evaluation experiments, the inclusion of 912 recipients provided a power of 90% to detect a difference of 14 days in the median GVHD score of 5 with an error of <0.05 between control and treated groups. For all experiments, a control group received TCD bone marrow alone without additional T cells, which controlled for the presence of T cells in the marrow inoculum and potential infectious complications during aplasia.

Animals were euthanized with CO2 followed by cervical dislocation,and spleen, liver, lungs, mesenteric lymph nodes (mLN), and lamina propria (LP) were excised. LP lymphocytes were isolated using the Miltenyi LP dissociation kit (catalog 130-097-410) as per the manufacturers instructions. Livers and lungs were digested in a solution of 1mg/ml collagenase A (Roche) and 75 U DNase I (Sigma-Aldrich) in RPMI 1640 with 5% newborn calf serum. Digested tissues were treated with ACK lysis buffer to remove RBCs and were passed through 100m cell strainers. Leukocytes were collected at the interface of a 40%:80% Percoll (Sigma-Aldrich) gradient in RPMI 1640 with 5% NCS. The pelleted cells were washed in 1x DPBS with 2% FBS. Spleens and mLN were teased apart, treated with ACK lysis buffer, and washed in 1 x DPBS with 2% FBS.

Animals were sacrificed, and lymphocytes were isolated from the SI, mLN, and IP lavage as described above. Single-cell suspensions were stained with an e450 Lineage antibody cocktail (Invitrogen, 88-7772-72) and BD Horizon AlexaFluor 700 Fixable Viability Stain (BD 564997). Cells were sorted based on GFP expression on a BD FACSAria II (BD Bioscience), and GFP+ cells were collected into cR10 prior to downstream processing.

Peripheral blood samples were collected from 12 adults who underwent HSCT at the Duke Adult Bone Marrow Transplant Clinic in Durham, NC between January 2015 and April 2017. All patients signed informed consent under Duke University IRB study protocol Pro00110250. Of the patients who remained stable after allo-HSCT, two out of three received myeloablative conditioning regiments while one underwent non-myeloablative conditioning. Similarly, of the patients who remained went on to experience an episode of acute GVHD in the first four months following their allo-HSCT, two out of three received myeloablative conditioning regiments while one underwent non-myeloablative conditioning. The average patient age at the time of HSCT was 56 years, and all included patients had a transplant indication of myelodysplastic syndrome. Sex and/or gender were not considered in the study design as specimen selection was limited to a small pool of experimentally eligible samples. All patients received calcineurin inhibition and short-course methotrexate for GvHD prophylaxis. We requested samples from 36 patients after alloHSCT with a diagnosis of acute graft-versus-host disease and 36 that were stable. In addition, we requested a pre-HSCT sample and then one drawn as close as possible to the time of the aGVHD diagnosis, as well as 3 months and 1 year where available.

2.55x106 cells were pelleted prior to fixation with and fixed with a 1% formaldehyde using the ChIP-IT High Sensitivity Kit (Active Motif). After quenching and washing, pellets were frozen at 80C. Upon thawing, cells were sheared using a chilled dounce homogenizer using with the ChIP-IT High Sensitivity Kit (Active Motif), and lysed cells were sonicated with nanodroplets for 60s with the Covaris Le220 prior to clarified by centrifuging at full speed for 15min. Input DNA was prepared with RNase A and Proteinase K prior to clean up and concentration with the Zymo Chip DNA Clean and Concentrate kit. 1030ug of ILC chromatin were treated with an anti-H3K4me3 antibody (Cell Signaling Technologies, rabbit mAb 9751, clone C42D8)+blocker mix along with a protease inhibitor cocktail prior to overnight end-to-end rotation at 4C. 30L of Protein G Dynabeads were added to each 240L immunoprecipitation reaction, and reactions were incubated for 3h. Samples were passed through a ChIP Filtration Column and then washed 5x with Wash Buffer AM1. After the removal of the residual wash buffer, samples were eluted in pre-warmed elution buffer AM4. De-crosslinking was carried out for 2.5h with Proteinase K prior to DNA extraction with the ChIP DNA Clean & Concentrator (Zymo Research) protocol. Chromatin immunoprecipitation quantitative real-time PCR (ChIP-qPCR) was performed using the QuantStudio 6K from Applied Biosystems.

Cells of interest were prepared in suspension and nuclei were isolated by pelleting 25,000200,000 in a fixed-angle centrifuge. Cells were lysed with 10mM Tris-HCl (pH 7.4), 10mM NaCl, and 3mM MgCl2 prior to 30min of transposition with an in house Tn5 transposase (generated at UNC CICBDD with Addgene construct #60240 as adapted from Picelli et al., Genome Res, 2014)30 at 37C. Immediately following transposition, samples were purified with Zymo Conc & Clean (Genesee) and stored at 20C prior to library amplification. Fragments were amplified using 1 NEBnext PCR master mix (New England BioSciences) and custom Nextera PCR primers 1 and 2 (Illumina, Supplementary Data3). Full libraries were amplified for five cycles (Thermo Fisher), after which a test aliquot of each sample was taken to test 20 cycles to determine the additional number of cycles needed for the remaining 45L reaction (QuantStudio 6K, Applied Biosystems). After the additional cycles were complete (average of 515 additional cycles), libraries were purified using a Zymo Conc & Clean (Genesee) prior to a two-sided Ampure bead (Beckman Coulter) size selection to enrich nucleosome-free fragments. Fragment size and concentration were determined by TapeStation 2000 and Qubit 4 (Agilent). Following QAQC, samples were sequenced on the Illumina HiSeq4000 (75x paired-end HO).

Following FACS sorting, paired multiome Single Cell ATAC (scATAC) and Single Cell Gene Expression (scGEX) libraries were prepared using the 10x Chromium Single Cell Multiome ATAC+Gene Expression kit (CG000338) with the low cell input nuclei isolation protocol (CG000365 Rev C). Lysis buffer strength was 1X, and lysis time was 4min. Multiome ATAC libraries (50x8x24x9) and GEX libraries (28x8x24x9) were sequenced at a depth of 2550,000 read pairs per cell on either the Illumina NextSeq2000P2 or Illumina NovaSeq SP.

The expression of Type 1 and Type 2 lineage-defining and lineage-associated genes was assessed in ex vivo expanded ILC2s and pcILC2s via quantitative real-time polymerase chain reaction (qRT-PCR) was performed with the RT2 Profiler PCR Array system (Qiagen, Hilden, Germany). Briefly, ILC2 and pcILC2 cells were cultured as described above and RNA was extracted after 6 days of expansion with the RNeasy Mini Kit (Qiagen). cDNA synthesis and genomic DNA elimination were performed with the RT2 First Strand Kit (Qiagen). cDNA was applied to the RT Profiler PCR Array Mouse Th1 & Th2 Response kit (PAMM-034Z; Qiagen) and PCR amplification was performed using RT2 SYBR Green qPCR Mastermix (Qiagen). Raw CT values were uploaded to Qiagens web-based software GeneGlobe, wherenormalization was performed by comparing to the internal housekeeping gene panel, and relative mRNA expression in the ILC2s and pcILC2s was calculated via the CT method.

Adapter sequences were removed from reads using cutadapt (v. 1.12). Reads were quality filtered using FASTX-ToolKit (v0.0.12) passing options Q 33, -p 90, and q 20. Reads were aligned to the mm10 genome using STAR (v2.5.2b) with the options: --outFilterScoreMin 1, --outFilterMultimapNmax 1 --outFilterMismatchNmax 2, --chimJunctionOverhangMin 15, --outSAMtype BAM Unsorted, --outFilterType BySJout, --chimSegmentMin 1. Read per million (RPM) normalized H3K4me3 signal at gene (RefSeq) promoters was calculated using deepTools (v.3.5.2), with the promoter region being defined as +300bp from mm10 RefSeq TSS to 500bp. Published H3K4me3 fastq files were downloaded from a public repository (GEO: GSE85156)8 and were aligned to the mm10 genome as described above. H3K4me3 peaks were identified using MACS2 (v.2.1.2, using default parameters)9 for all subpopulations of ILCs (two replicates each). Differential H3K4me3 marked promoters were identified through the application of DEseq2 (Likelihood ratio test, v.1.40.2)31 on the union set of peaks. Multiple testing was mitigated using the Benjamini and Hochberg method. ILC1, ILC2, and ILC3-specific H3K4me3 marked promoters were identified by hierarchical clustering of differential promoters. Representative tracks were created by passing RPM normalized bigwig files to the UCSC Genome Browser.

Data from Bruce et al. J Clin Invest, 127(5):1813-1825. doi: 10.1172/JCI91816, PMID: 28375154. FASTQ files were downloaded from GEO (GSE95811)4. Adapter sequences were removed using (cutadapt v1.12). Reads were quality filtered using fastq quality filter in FASTX-Toolkit (v0.0.12) with options -Q 33, -p 90, and q 20. Reads were aligned to mm10 genome using STAR (v2.5.2b) with the following options: --quantMode TranscriptomeSAM, --outFilterMismatchNmax 2, --alignIntronMax 1000000, --alignIntronMin 20, --chimSegmentMin 15, --chimJunctionOverhangMin 15, --outSAMtype BAM Unsorted, --outFilterType BySJout, --outFilterScoreMin 1. Transcript-level expression values (TPM) were estimated using Salmon (v0.11.3) for RefSeq transcripts. TPM data was collapsed into gene-level expression values using a tximport. Refseq was used for gene annotation.

Sequence adapters were trimmed using cutadapt (v. 1.12) with the following options -a CTGTCTCTTATA -A CTGTCTCTTATA and --minimum-length 36 and set for paired-end sequence data. Reads were then quality filtered using fastq_quality_filter in FASTX-Toolkit (v. 0.0.14), with the options -Q 33, -p 90, and -q 20. PCR duplicates were restricted by limiting the same sequence to a max of 5 copies. After this duplicate threshold was reached, the remaining reads were excluded (In house scripts). As one read of a read-pair may have been excluded during filtering, fastq files were synced following the filtering step to ensure accurate alignment. Reads were aligned to either mm10 or hg38 using STAR (v2.5.2b) with options chimSegmentMin 15, --outFilterMismatchNmax 2, --chimJunctionOverhangMin 15, --outSAMtype BAM Unsorted, --outFilterScoreMin 1, --outFilterType BySJout and --outFilterMultimapNmax 1. Samtools (v. 1.3.1) and bedtools (v. 2.26) were then used to create bigwig files. These files only include fragment data for the first 5bp from the 5 end and the last 4bp from the 3 end of fragments. Regions of chromatin accessibility (peaks) were defined using MACS (v. 2.1.2) with options nomodel, --shift 0, --extsize 5. Sites of differential chromatin accessibility were identified using DESeq2 (v. 1.40.2) with default parameters using a union set of peaks. Motif analysis was performed using findMotifsGenome.pl from HOMER (v. 4.11.1). Representative tracks of normalized ATAC signal were generated by visualizing bigwig files on the UCSC genome browser.

From Gury-BenAri et al. Cell, 2016, 166(5):1231-1246.e13, doi: 10.1016/j.cell.2016.07.043, PMID: 27545347. The UMI count table was downloaded from GEO (GSE85152). The count table was calculated as previously described8. The first gene name was selected to represent features when more than one possible annotation was available. Cells with less than 200 UMIs were discarded from downstream analysis.

Paired-end FASTQ files were pre-processed and aligned to the mouse reference genome (GRCm38/mm10) using cellranger-arc count (v. 2.0.0) with default parameters. Next, we selected nuclei with a total RNA read count <25,000, total RNA read count >1000, total ATAC read count <70,000, total ATAC read count >5000, and mitochondrial counts <20% for downstream analysis. We then integrated the datasets using RNA data only or with both RNA and ATAC. Integration using RNA was accomplished using the IntegrateData function within Seurat passing default parameters (v. 4.3.0.1)10. The dimensionality of the data was reduced using principal component analysis (PCA), and Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP). Cells were then clustered using the FindClusters function within Seurat. Prior to the integration of multi-modality data, the RNA and ATAC count matrices for each sample were merged. The merge function within Seurat was used to concatenate the RNA count matrices. To create the merged ATAC count matrix, we first identified a union set of peaks across all samples and calculated the number of ATAC fragments overlapping those shared genomic coordinates for each sample using FeatureMatrix (Signac v. 1.10.0). The RNA and ATAC count matrices were then merged by sample, and the data were integrated using the Weighted nearest neighbor analysis (Seurat) to develop shared inference32. Differentially expressed genes were identified using a Wilcoxon rank sum test as implemented in the package presto (v. 1.0.0) or with the FindMarkers function in Seurat. Heatmap of differentially expressed genes depicts mean-centered and normalized RNA abundance. Normalized (SCTransform) and uncorrected (pre-integration) RNA counts were used for differential testing. A 2-cell cluster (pre- and post-transplant mouse data, AAGGATTAGCTCATAA-1_2, AGTGGACAGCTATTAG-1_2) was identified and excluded from downstream analysis. To determine differential regions of chromatin accessibility, we also used a Wilcoxon rank sum test (presto, v. 1.0.0) on TF-IDF normalized ATAC counts. Heatmap of differential regions of chromatin accessibility depicts mean-centered and normalized ATAC signal. Per-cell accessibility for motifs (motif enrichment scores) was calculated using the package chromVAR (v. 1.22.1). The JASPER 2020, CORE, vertebrate motif database was used during motif identification. To identify putative TF regulators for each cluster of cells, the AUC statistics calculated by presto during the differential expression and differential motif enrichment analysis (Wilcox rank sum test (p adj <0.05, RNA.logFC> 0 and motif.p adj <0.05, motif.logFC> 0)) were averaged, and the TFs with the highest value were considered top candidates. Average per-cell chromatin accessibility (ATAC signal) across genes previously associated with ILC1 and ILC2 isolated from small intestinal lamina propria of mice8 was calculated using the FeatureMatrix from the Signac Package. For ontology analysis, we used Enrichr33 and tested for significant overlap between genes associated with post-transplant cells and gene sets found in the mouse gene atlas database. The average marker expression of ILC1, ILC2, ILC3, and NK cells was defined by averaging the normalized gene expression for genes previously associated with each cell type11. Classification of post-transplant cells as ILC1, ILC2, or ILC3 was based on lineage defining genes previously associated with each type of ILC8. Seurat was used to integrate post-transplant single nucleus RNA data with previously published8 MARS-seq RNA abundance data as previously described10. Cells were classified by calculating the average rank of genes associated with each type of ILC and labeling each cell with the cell type with the highest rank. Undetermined signifies a tie in ranking. Upset plots were created using UpSetR (v. 1.4.0).

Paired-end FASTQ files were pre-processed and aligned to the mouse (GRCm38/mm10) or human reference genome (GRCh38/hg38) using cellranger-atac count (v. 2.0.0) with default parameters. To compare the average normalized ATAC signal across each patient sample at hILC2 sites of CA (defied with bulk ATAC data), we first calculated the number of ATAC fragments overlapping the 7456 associated sites of CA using FeatureMatrix (Seurat, v. 4.3.0.1), respectively. We then merged these count matrices and normalized the data using TF-IDF as implemented in Seurat (v. 4.3.0.1). The same operations were performed for the pc-hILC2 associated sites of CA (n=5,051) as well as random sites (n=7,456) of chromatin accessibility shared between hILC2 and pc-hILC2s. Samples were grouped into six patient conditions, four according to transplant status and aGVHD, two healthy donors, and expanded ILC2s derived from an additional single healthy donor. Differential ATAC was tested using patient condition as a categorical variable in a linear model. The model was fit in R and the coefficients were evaluated to highlight different effects for patient conditions. We then grouped the sample into four categories: healthy donor, ILC2, pre- and post-transplant samples (independent of aGVHD) and repeated the above analysis. For both tests, we assessed significance using p<0.05. Identification of genes with differential ATAC signals between pre- and post-transplant patients was performed using the sum of ATAC signals at each gene for all patient samples (calculated with FeatureMatrix). The 6 pre-transplant and 6 post-transplant samples were then analyzed as biological replicates of each condition, and differential analysis was performed using DESeq2. Ontology analyses were performed using g:profiler (v. 0.2.2)34. For differential analysis of aggregate ATAC signal for each gene average ATAC signal was defined as the total normalized ATAC signal over all gene bodies plus 2kb upstream for all pre- (n=6) and post-transplant (n=6) patient samples. Genes with differential ATAC signals were then identified using DESeq2.

Survival differences were evaluated using a Mantel-Cox log-rank test. Survival curves were generated using the Kaplan-Meier method. Differences in GVHD clinical and pathology scores were determined using 2-way ANOVA, with Bonferroni correction for repeated measures of multiple comparisons. Statistical analysis of ATAC-seq and RNA-seq data is described above. Unless otherwise noted in the figure legends, all other continuous variables were compared using a 2-tailed Students t test with Welchs correction. A P-value of 0.05 was considered statistically significant.

Further information on research design is available in theNature Portfolio Reporting Summary linked to this article.

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Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation - Nature.com

Close-up of hematopoietic niche in bone marrow: artsakon - stock.adobe.com

The BLA of tab-cel, an off-the-shelf, allogeneic, T-cell immunotherapy, has been accepted and granted priority review by the FDA for the treatment of adult and pediatric patients aged 2 years and older with EBV+ PTLD who have received at least 1 prior therapy. A PDUFA target action date of January 15, 2025, has been set.1

There are currently no FDA-approved therapies in this setting, marking a notable unmet need for patients.

The acceptance of the tab-cel BLA is a significant milestone towards making this first-of-its-kind treatment available to patients in the US, said Pascal Touchon, president and chief executive officer of Atara, in a press release. The FDAs granting of priority review highlights the high unmet need in EBV+ PTLD, which is a devastating disease with limited treatment options and a poor overall survival rate. We continue to work closely with the Pierre Fabre Laboratories team to help prepare for the potential launch in the US in early 2025, along with the potential label expansion multicohort phase 2 EBVision trial [NCT04554914].

The BLA is supported by data from the phase 3 ALLELE study (NCT03394365). The study investigated tab-cel in 43 patients with EBV+ PTLD following hematopoietic cell transplant (HCT) or solid organ transplant (SOT) after rituximab (Rituxan) and chemotherapy failed. Patients received tab-cel at 2 x 106 cells/kg on days 1, 8, and 15 of 35-day cycles.2

The overall response rate (ORR) was 51.2% (95% CI, 35.5%-66.7%). The ORR in patients who underwent HCT (n = 14) was 50.0% (95% CI, 23.0%-77.0%), and 51.7% (95% CI, 32.5%-70.6%) in patients who received SOT (n = 29). The median time to response was 1.0 month (range, 0.7-4.7). Out of the 22 responders, 12 had a duration of response (DOR) longer than 6 months, and the median DOR was 23.0 months (95% CI, 6.8-not evaluable [NE]).

The median overall survival (OS) was 18.4 months (95% CI, 6.9-NE) in the overall population, not reached in the HCT population (95% CI, 5.7-NE), and 16.4 months (95% CI, 5.0-NE) in the SOT population. One-year OS rates were 61.1% (95% CI, 43.7%-74.5%) in the overall population, 70.1% (95% CI, 38.5%-87.6%) with HCT, and 56.2% (95% CI, 34.6%-73.2%) with SOT.

Regarding safety, serious treatment-emergent adverse events (TEAEs) were reported in 57.1% of patients in the HCT group, and 7.1% of patients experienced a fatal TEAE. In the SOT group, 51.7% and 13.8% experienced serious and fatal TEAEs, respectively. No fatal TEAEs were deemed related to treatment. There were no reports of tumor flare reactions, infusion reactions, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, marrow rejection, or transmission of infectious diseases. There were no reports of graft-vs-host disease or organ rejection that were considered related to tab-cel.

Previously, tab-cel was granted FDA breakthrough therapy designation and orphan drug designation for the treatment of rituximab-refractory EBV-associated lymphoproliferative disease.1

Original post:
FDA Accepts Application of Tab-Cel, First-in-Class Therapy for EBV+ PTLD - Targeted Oncology

A German man has probably been cured of HIV, a medical milestone achieved by only six other people in the more than 40 years since the AIDS epidemic began.

The German man, who prefers to remain anonymous, was treated for acute myeloid leukemia, or AML, with a stem cell transplant in October 2015. He stopped taking his antiretroviral drugs in September 2018 and remains in viral remission with no rebound. Multiple ultra-sensitive tests have detected no viable HIV in his body.

In a statement, the man said of his remission: A healthy person has many wishes, a sick person only one.

The case, which investigators said offered vital lessons for HIV cure research, is expected to be presented Wednesday by Dr. Christian Gaebler, a physician-scientist at the Charit-Universittsmedizin Berlin, at the 25th International AIDS Conference in Munich.

The longer we see these HIV remissions without any HIV therapy, the more confidence we can get that were probably seeing a case where we really have eradicated all competent HIV, Gaebler said.

As with all previous cases of potential HIV cure, experts are eager to temper public excitement with a caveat: The treatment that apparently thwarted the virus in the seven patients will ever be available to only a select few. All contracted HIV and later developed blood cancer, which demanded stem cell transplants to treat the malignancy.

The transplants in most cases from donors selected because their immune cells, the cells that HIV targets boasted a rare, natural resistance to the virus and were instrumental in apparently eradicating all viable, or competent, copies of the virus from the body.

Stem cell transplants are highly toxic and can be fatal. So it would be unethical to provide them to people with HIV except to treat separate diseases, like blood cancer.

HIV is monumentally difficult to cure because some of the cells it infects are long-living immune cells that are in or enter a dormant state. Standard antiretroviral treatment for HIV works only on immune cells that, typical of infected cells, are actively making new viral copies. Consequently, HIV within resting cells stays under the radar. Collectively, such cells are known as the viral reservoir.

At any moment, a reservoir cell can start producing HIV. That is why if people with the virus stop taking their antiretrovirals, their viral loads typically rebound within weeks.

A stem cell transplant has the potential to cure HIV in part because it requires destroying a persons cancer-afflicted immune system with chemotherapy and sometimes radiation and replacing it with a donors healthy immune system.

In five of the seven cases of definite or possible HIV cure, doctors found donors who had rare, natural defects in both copies of a gene that gives rise to a particular protein, called CCR5, on the surface of immune cells. Most HIV strains attach to that protein to infect cells. Without functional CCR5 proteins, immune cells are HIV-resistant.

The German mans donor had just one copy of the CCR5 gene, meaning his immune cells most likely have about half the normal quantity of that protein. In addition, he had only one copy of the gene himself. Together, those two genetic factors may have upped his chances of a cure, Gaebler said.

While having two copies of the defective CCR5 gene is rare, occurring in about 1% of people with native northern European ancestry, having one copy occurs in about 16% of such people.

So the study suggests that we can broaden the donor pool for these kinds of cases, Dr. Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, said in a media briefing last week.

Interestingly, a man treated in Geneva whose possible HIV cure was announced last year had a donor with two normal copies of the CCR5 gene. So his transplanted immune cells were not HIV-resistant.

Those two recent European cases raise critical questions about the factors that actually contribute to a successful HIV cure.

The level of protection one might have predicted from transplant should not have been enough to prevent the virus from surviving and rebounding, Dr. Steven Deeks, a leading HIV cure researcher at the University of California, San Francisco, who is not involved with the German mans care, said of his case. There are several testable theories, so I am optimistic we will learn something here that could shape the next generation of cure studies.

Gaebler said having HIV-resistant immune cells in the mix surely greatly improves the chances of success in curing the virus with a stem cell transplant. And yet, he said, lacking that safety net, or having one with some holes in it, as with the German man, does not preclude success.

We need to understand how the new immune system successfully grafted into his body and how it successfully eliminated HIV reservoirs over time, he said. Suggesting that the transplanted immune cells may have attacked the viral reservoir, he said, The donors innate immune system might have played an important role here.

All were initially known by pseudonyms based on where they were treated.

Adam Castillejo, aka the London patient. Castillejo, 44, a Venezuelan man living in England, received a stem cell transplant for AML in 2016 and stopped HIV treatment in 2017. He is considered cured.

Marc Franke, the Dsseldorf patient. Treated with a stem cell transplant for AML in 2013, Franke, 55, went off antiretrovirals in November 2018 and is considered cured.

Paul Edmonds, aka the City of Hope patient. Edmonds, the oldest potential cure case at 63 when he received a stem-cell transplant for AML in 2019, received reduced-intensity chemotherapy because of his age. Off antiretrovirals since March 2021, he will be considered cured when he hits five years with no viral rebound. In an interview, he expressed excitement over the new case of a man probably cured, as well, and said, My vision is clear: a world where HIV is no longer a sentence, but a footnote in history.

The New York patient. The first woman and person of mixed-race ancestry possibly to be cured, she was diagnosed with leukemia in 2017 and received a stem cell transplant augmented with umbilical cord blood, which allowed for a lower genetic match with her donor, thus broadening the donor pool.

The Geneva patient. In his 50s, he was diagnosed with a rare blood cancer in 2018 and has been off of HIV treatment since November 2021. Researchers remain cautious about his cure status because his immune cells are not HIV resistant.

Franke, Edmonds and Castillejo, who have become friends, are expected to attend the HIV conference in Munich.

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A 7th person with HIV is probably cured after stem cell transplant for leukemia, scientists say - AOL

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Seventh person likely 'cured' of HIV, doctors announce - El Paso Inc.

Li R, et al. Crosstalk between dendritic cells and regulatory T cells: protective effect and therapeutic potential in multiple sclerosis. Front Immunol. 2022;13: 970508.

Article CAS PubMed PubMed Central Google Scholar

Moser T, et al. The role of TH17 cells in multiple sclerosis: therapeutic implications. Autoimmun Rev. 2020;19(10): 102647.

Article CAS PubMed Google Scholar

Dimitriou NG, et al. Treatment of patients with multiple sclerosis transitioning between relapsing and progressive disease. CNS Drugs. 2023;37(1):6992.

Article PubMed PubMed Central Google Scholar

Ruiz F, Vigne S, Pot C. Resolution of inflammation during multiple sclerosis. Semin Immunopathol. 2019;41(6):71126.

Article CAS PubMed PubMed Central Google Scholar

Bar-Or A, Li R. Cellular immunology of relapsing multiple sclerosis: interactions, checks, and balances. Lancet Neurol. 2021;20(6):47083.

Article CAS PubMed Google Scholar

van Langelaar J, et al. B and T cells driving multiple sclerosis: identity, mechanisms and potential triggers. Front Immunol. 2020;11:760.

Article PubMed PubMed Central Google Scholar

Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):54558.

Article CAS PubMed Google Scholar

Karimi E, et al. LncRNA-miRNA network analysis across the Th17 cell line reveals biomarker potency of lncRNA NEAT1 and KCNQ1OT1 in multiple sclerosis. J Cell Mol Med. 2022;26(8):235162.

Article CAS PubMed PubMed Central Google Scholar

Shi C, et al. Trojan horse nanocapsule enabled in situ modulation of the phenotypic conversion of Th17 cells to Treg cells for the treatment of multiple sclerosis in mice. Adv Mater. 2023;35(11): e2210262.

Article PubMed Google Scholar

Fujiwara M, et al. microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance. J Clin Invest. 2022;132(10): e155693.

Article CAS PubMed PubMed Central Google Scholar

Grigoriadis N, van Pesch V, Paradig MSG. A basic overview of multiple sclerosis immunopathology. Eur J Neurol. 2015;22(Suppl 2):313.

Article PubMed Google Scholar

Charabati M, et al. DICAM promotes T(H)17 lymphocyte trafficking across the blood-brain barrier during autoimmune neuroinflammation. Sci Transl Med. 2022;14(626):eabj0473.

Article CAS PubMed Google Scholar

Shi Y, et al. Th17 cells and inflammation in neurological disorders: possible mechanisms of action. Front Immunol. 2022;13: 932152.

Article CAS PubMed PubMed Central Google Scholar

Balasa R, et al. The action of TH17 cells on blood brain barrier in multiple sclerosis and experimental autoimmune encephalomyelitis. Hum Immunol. 2020;81(5):23743.

Article CAS PubMed Google Scholar

Murphy AC, et al. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2010;24(4):64151.

Article CAS PubMed Google Scholar

Larochelle C, et al. Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation. Proc Natl Acad Sci U S A. 2021;118(34): e2025813118.

Article CAS PubMed PubMed Central Google Scholar

van Langelaar J, et al. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain. 2018;141(5):133449.

Article PubMed Google Scholar

Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117.

Article CAS PubMed PubMed Central Google Scholar

Rodriguez Murua S, Farez MF, Quintana FJ. The immune response in multiple sclerosis. Annu Rev Pathol. 2022;17:12139.

Article CAS PubMed Google Scholar

Zhu H, et al. Anlotinib attenuates experimental autoimmune encephalomyelitis mice model of multiple sclerosis via modulating the differentiation of Th17 and Treg cells. Immunopharmacol Immunotoxicol. 2022;44(4):594602.

Article PubMed Google Scholar

Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol. 2013;25(4):30512.

Article CAS PubMed PubMed Central Google Scholar

Wang D, et al. IFN-beta facilitates neuroantigen-dependent induction of CD25+ FOXP3+ regulatory T cells that suppress experimental autoimmune encephalomyelitis. J Immunol. 2016;197(8):29923007.

Article CAS PubMed Google Scholar

Melnikov M, et al. The influence of glatiramer acetate on Th17-immune response in multiple sclerosis. PLoS ONE. 2020;15(10): e0240305.

Article CAS PubMed PubMed Central Google Scholar

Correale J, et al. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017;140(3):52746.

PubMed Google Scholar

Tramacere I, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015;2015(9):CD011381.

PubMed PubMed Central Google Scholar

Luchtman DW, et al. IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: current and future developments. Cytokine Growth Factor Rev. 2014;25(4):40313.

Article CAS PubMed Google Scholar

Faissner S, Gold R. Oral therapies for multiple sclerosis. Cold Spring Harb Perspect Med. 2019;9(1): a032011.

Article CAS PubMed PubMed Central Google Scholar

Thne J, Linker RA. Laquinimod in the treatment of multiple sclerosis: a review of the data so far. Drug Des Devel Ther. 2016;10:11118.

Article PubMed PubMed Central Google Scholar

Chun J, Giovannoni G, Hunter SF. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects. Drugs. 2021;81(2):20731.

Article CAS PubMed Google Scholar

Melamed E, Lee MW. Multiple sclerosis and cancer: the Ying-Yang effect of disease modifying therapies. Front Immunol. 2019;10:2954.

Article CAS PubMed Google Scholar

Mariottini A, Muraro PA, Lunemann JD. Antibody-mediated cell depletion therapies in multiple sclerosis. Front Immunol. 2022;13: 953649.

Article CAS PubMed PubMed Central Google Scholar

Glatigny S, Bettelli E. Experimental autoimmune encephalomyelitis (EAE) as animal models of multiple sclerosis (MS). Cold Spring Harb Perspect Med. 2018;8(11): a028977.

Article CAS PubMed PubMed Central Google Scholar

Othy S, et al. Regulatory T cells suppress Th17 cell Ca(2+) signaling in the spinal cord during murine autoimmune neuroinflammation. Proc Natl Acad Sci U S A. 2020;117(33):2008899.

Article CAS PubMed PubMed Central Google Scholar

Prado DS, et al. Pitavastatin ameliorates autoimmune neuroinflammation by regulating the Treg/Th17 cell balance through inhibition of mevalonate metabolism. Int Immunopharmacol. 2021;91: 107278.

Article CAS PubMed Google Scholar

Jin B, et al. Therapeutic effect of ginsenoside rd on experimental autoimmune encephalomyelitis model mice: regulation of inflammation and Treg/Th17 cell balance. Mediators Inflamm. 2020;2020:8827527.

Article PubMed PubMed Central Google Scholar

Li Z, et al. Rapamycin relieves inflammation of experimental autoimmune encephalomyelitis by altering the balance of Treg/Th17 in a mouse model. Neurosci Lett. 2019;705:3945.

Article CAS PubMed Google Scholar

Wang Y, et al. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell. 2022;29(11):151530.

Article CAS PubMed Google Scholar

Huang Y, Wu Q, Tam PKH. Immunomodulatory mechanisms of mesenchymal stem cells and their potential clinical applications. Int J Mol Sci. 2022;23(17):10023.

Article CAS PubMed PubMed Central Google Scholar

Liu P, et al. Mesenchymal stem cells: emerging concepts and recent advances in their roles in organismal homeostasis and therapy. Front Cell Infect Microbiol. 2023;13:1131218.

Article CAS PubMed PubMed Central Google Scholar

Wang L, et al. Regulation of inflammatory cytokine storms by mesenchymal stem cells. Front Immunol. 2021;12: 726909.

Article CAS PubMed PubMed Central Google Scholar

Alanazi A, et al. Mesenchymal stem cell therapy: a review of clinical trials for multiple sclerosis. Regen Ther. 2022;21:2019.

Article CAS PubMed PubMed Central Google Scholar

Shokati A, et al. A focus on allogeneic mesenchymal stromal cells as a versatile therapeutic tool for treating multiple sclerosis. Stem Cell Res Ther. 2021;12(1):400.

Article PubMed PubMed Central Google Scholar

Jasim SA, et al. Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune diseases. Stem Cell Res Ther. 2022;13(1):101.

Article PubMed PubMed Central Google Scholar

Haghmorad D, et al. Bone marrow mesenchymal stem cells to ameliorate experimental autoimmune encephalomyelitis via modifying expression patterns of miRNAs. Mol Biol Rep. 2023;50(12):997184.

Article CAS PubMed Google Scholar

Regen T, Waisman A. Modeling a complex disease: multiple sclerosis-Update 2020. Adv Immunol. 2021;149:2534.

Article CAS PubMed Google Scholar

Kaskow BJ, Baecher-Allan C. Effector T cells in multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(4): a029025.

Article PubMed PubMed Central Google Scholar

Melnikov M, et al. Dopaminergic therapeutics in multiple sclerosis: focus on Th17-cell functions. J Neuroimmune Pharmacol. 2020;15(1):3747.

Article PubMed Google Scholar

Rostami A, Ciric B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J Neurol Sci. 2013;333(12):7687.

Article CAS PubMed PubMed Central Google Scholar

Wojkowska DW, et al. Interactions between neutrophils, Th17 cells, and chemokines during the initiation of experimental model of multiple sclerosis. Mediators Inflamm. 2014;2014: 590409.

Article PubMed PubMed Central Google Scholar

Restorick SM, et al. CCR6(+) Th cells in the cerebrospinal fluid of persons with multiple sclerosis are dominated by pathogenic non-classic Th1 cells and GM-CSF-only-secreting Th cells. Brain Behav Immun. 2017;64:719.

Article CAS PubMed PubMed Central Google Scholar

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This new model, which mimics human bone marrow, could offer a novel approach to testing drugs and techniques for treating blood disorders like sickle cell disease and blood cancers

Scientists from the University of Glasgow have developed the first bioengineered bone marrow model capable of supporting long-term hematopoietic stem cells (LT-HSCs), essential for bone marrow transplants and in vitro studies.

This groundbreaking research, published in Nature Communications, replicates key aspects of the human bone marrow microenvironment, enabling the support and culture of these rare stem cells outside the human body.

LT-HSCs are crucial for bone marrow transplants as they can replenish blood cells after treatments for blood cancers. However, culturing these cells in the lab has been challenging as they quickly change or die once outside the body. Due to this limitation, scientists have to rely on non-human animal models to test drugs affecting blood cell production and targeting blood diseases such as leukaemias. These models often provide poor predictions of drug outcomes.

In the study, led by Dr. Hannah Donnelly, LT-HSCs were cultured out of the body by using specially engineered gels mimicking the bone marrow environment.

Dr Donnelly said: LT-HSCs are notoriously difficult to culture outside the body yet hold enormous clinical value.

Here, we show that by using gels engineered to mimic the environment where they reside in the bone marrow, we can support and study these cells in the lab, ultimately harnessing their full clinical potential.

The scientists showed that gene editing of LT-HSCs in these gels is feasible, potentially offering a new way to test new drugs and techniques for treating blood disorders such as sickle cell disease and blood cancers, thus reducing dependence on animal models.

Professor Matt Dalby, Director of Innovation, Engagement, and Enterprise at the School of Molecular Biosciences, University of Glasgow, highlighted the impact of their research on drug testing: Currently used animal models are poor predictors of drug outcomes, and many of the blood disease treatments on offer such as mRNA drugs and human-specific small molecules dont test well in animal models.

By creating ambitious models of the bone marrow which contain human cells and have the ability to mimic blood cell growth we are thrilled to show for the first time that it is possible to test true human blood cells out with the human body, and the implications for accelerating therapies for diseases such as sickle cell disease and blood cancers gives us huge reason to be hopeful.

Professor Manuel Salmeron Sanchez, Chair of Biomedical Engineering and Head of the School of Engineering, added that the use of this new model, which mimics bone marrow will allow them to focus on the earliest stages of diseases, providing new understanding, screening methods, and drugs.

This research is part of a major investment in leukemia research in the UK, funded by the UKRIs Engineering and Physical Sciences Research Council (EPSRC). Leukaemia kills over 300,000 people globally each year, but early diagnosis of the disease remains a challenge, which reduces the impact of treatments.

The study titled Bioengineered niches that recreate physiological extracellular matrix organization to support long-term haematopoietic stem cells, provides hope for better understanding, diagnosis, and treatment of blood disorders and cancers.

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New bioengineered bone marrow model offers hope for blood cancer therapy - Pharmacy Business

Jul 19, 2024 14:00:00

A German HIV patient has been symptom-free for six years after undergoing a stem cell transplant, making him likely the seventh person to be essentially cured of HIV after receiving a stem cell transplant, doctors have announced.

Seventh person likely 'cured' of HIV, doctors announce

According to the research abstract, the German man in long-term remission was first diagnosed with HIV in 2009, underwent a bone marrow transplant for leukemia in 2015, and then stopped taking antiretroviral drugs to reduce the amount of HIV in his blood in 2018. Nearly six years have passed since then, and he has been deemed to have achieved long-term remission as he has not developed HIV or cancer.

'We can never be absolutely certain that the last traces of HIV have been eradicated,' said Dr. Christian Gabler of Charit University Hospital, who treated the patient. 'However, this patient's case is a strong indicator of HIV cure.'

'Researchers are hesitant to use the word 'cure' because it's not clear how long cases like this need to be followed for, but more than five years in remission means this man is 'near cure,'' said Sharon Lewin, president of the International AIDS Society.

Lewin said there's an important difference between this man's case and other HIV patients who have achieved long-term remission: All but one of them reportedly received stem cells from donors who carried a rare mutation that stops HIV from entering the body's cells.

All of these donors were found to have a defective CCR5 gene, meaning they had inherited two copies of the mutated gene (one from each parent), which gave them 'intrinsic immunity to HIV,' Lewin said.

However, this patient is the first to have received stem cells from a donor who inherited only one mutated gene.

While only 1% of Europeans have inherited two copies of the mutated CCR5 gene, as many as 15% have only one, which suggests that more donors may be accepted in the future, the researchers said.

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Doctors say 60-year-old German man likely to become seventh person in the world cured of HIV - GIGAZINE

Myelodysplastic neoplasms (MDS) are hematopoietic stem cell disorders characterized by ineffective hematopoiesis and dysplastic cells in the bone marrow (BM) [1]. In addition, patients with MDS display an increased susceptibility to osteoporosis [2]. Evidence points towards dysregulation in the BM niche that concurrently impairs bone turnover and hematopoiesis. We identified fibroblast growth factor (FGF)-23 as a critical regulator of bone mineralization and erythropoiesis. FGF-23 serum levels were higher in both patients and mice with MDS, and its neutralization resulted in improved erythropoiesis and bone mineralization in NUP98/HOXD13 (NHD13) mice [3]. FGF-23 is mainly produced by osteoblasts/osteocytes [4] and exerts phosphaturic effects leading to poor bone mineralization [5]. However, in NHD13 mice, intact FGF-23 (iFGF-23) and C-terminal FGF-23 (cFGF-23; produced by the cleavage of the intact form) protein levels were unchanged in the bone tissue, but erythroid progenitors secreted more FGF-23 compared to littermate wild-type (WT) controls (Fig.S1A, B).

Here, we tested the hypothesis that erythroid precursors contribute to increased FGF-23 production/cleavage in MDS as a cause for impaired erythropoiesis and bone mineralization. To that end, we used BM transplantation as a first approach to substitute myelodysplastic erythroblasts with healthy ones in NHD13 mice. Four months after the BM transplantation, all mice that received the NHD13 BM showed MDS-like symptoms. In WT recipients, a reduction in hemoglobin levels [32%; p<0.001], platelets [20%; p<0.05], and lymphocytes [71%; p<0.001], but not in neutrophils or monocytes was observed compared to WT controls (transplanted with WT BM), showing a similar MDS status as NHD13 controls. In turn, NHD13 mice transplanted with WT BM did not develop MDS during the observation period. Compared to NHD13 controls, blood count reached normal levels [hemoglobin: +22%; p<0.001; platelets: +26%; p<0.05; lymphocytes: +6.5-fold; p<0.001; neutrophils: +2-fold; p<0.001] (Fig.1AE). This confirms that the MDS blood phenotype is transferable via hematopoietic cells. In line with NHD13 mice only showing increased cFGF-23 levels, but normal serum levels of iFGF-23 [3], the transplantation of WT or NHD13 BM into either WT or NHD13 recipient mice did not alter iFGF-23 (Fig.1F). In contrast, cFGF-23 was increased in all recipients of NHD13 BM [WT: +3.5-fold; p<0.05; NHD13: +2.1-fold; p<0.01] compared to the corresponding mice with WT BM (Fig.1G). Because of the transferable FGF-23 status, we hypothesized that WT mice receiving NHD13 BM would exhibit a bone phenotype mimicking the NHD13 controls. That was the case regarding the increased bone formation parameters usually observed in NHD13 mice. Similar to NHD13 mice, WT mice receiving NHD13 BM showed an increased number of osteoblasts [+95%; p<0.001] concomitant with elevated levels of the bone formation marker procollagen type I N-propeptide [+45%; p<0.05] and an increased bone formation rate [+87%; p<0.01] (Fig.1HJ). Also, the osteoid surface per bone surface tended to be increased [+44%; p=0.056] (Fig.1K). Importantly, transplanting WT BM to NHD13 mice normalized their bone formation parameters (Fig.1HK), indicating that hematopoietic cell signals control bone formation in NHD13 mice.

Eigth-week-old male wild-type (WT) and NUP98/HOXD13 (NHD13) mice were lethally irradiated one day before 2106 total bone marrow cells of age-matched WT (WT BM) or NHD13 (NHD13 BM) donor mice were transplanted by intravenous injection. After 16 weeks all mice were sacrificed and analyzed. The blood count, (A) hemoglobin levels (WT BMWT: n=9; NHD13 BMWT: n=9; WT BMNHD13: n=14; NHD13 BMNHD13: n=8), (B) platelet number (WT BMWT: n=8; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=7) as well as the number of (C) neutrophils, (D) lymphocytes (WT BMWT: n=8; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=8), and (E) monocytes (WT BMWT: n=8; NHD13 BMWT: n=7; WT BMNHD13: n=15; NHD13 BMNHD13: n=7) were received using the Sysmex XN-100 (Sysmex, Norderstedt, Germany). After collecting the serum, (F) the intact (WT BMWT: n=9; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=9) as well as (G) C-terminal fibroblast growth factor (FGF)-23 (WT BMWT: n=8; NHD13 BMWT: n=6; WT BMNHD13: n=13; NHD13 BMNHD13: n=8) were measured by ELISA. (H) The osteoblasts per bone perimeter were evaluated in TRAP-stained vertebral bone slices (WT BMWT: n=9; NHD13 BMWT: n=9; WT BMNHD13: n=14; NHD13 BMNHD13: n=9) and (I) the osteoblast activity was assessed by procollagen type I N-propeptide (P1NP) using ELISA (WT BMWT: n=8; NHD13 BMWT: n=9; WT BMNHD13: n=14; NHD13 BMNHD13: n=9). J To determine the bone formation rate in vertebrae, mice received intraperitoneal calcein injection 5 and 2 days before sacrifice for the double labeling analysis (WT BMWT: n=9; NHD13 BMWT: n=6; WT BMNHD13: n=13; NHD13 BMNHD13: n=6). K Embedded vertebrae were stained with von Kossa/van Gieson to determine the osteoid surface per bone surface (WT BMWT: n=6; NHD13 BMWT: n=8; WT BMNHD13: n=14; NHD13 BMNHD13: n=5). Data are shown as meanSD of five independent experiments. Statistical analysis was performed by two-sided Students t test. *p<0.05; **p<0.01; ***p<0.001.

To address whether stem cell transplantation (SCT) leads to similar changes in FGF-23 in patients with MDS, we employed samples from the BoHemE study, in which we previously confirmed the high plasma iFGF-23 and cFGF-23 levels in patients with MDS [3]. Within this cohort, we identified 10 patients with MDS (3 women, 7 men; median age: 64 years; without renal disease) who had undergone SCT. We analyzed their hematological and bone-specific parameters before (range: 16 months) and after SCT (range: 511 months). SCT led to a higher number of red blood cells in 9/10 patients, neutrophils in 9/10 patients, and lymphocytes in 6/10 patients with normal monocyte counts. Platelet counts were below the reference range in 8/10 patients and higher in 1/10 patients before SCT, but only 4 patients had persistent thrombocytopenia after SCT (Figs.2A, S2AD). Before SCT, 5 patients showed elevated cFGF-23 plasma levels, which were normalized after SCT (Fig.2B). Elevated iFGF-23 levels were observed in 2 patients before SCT, with levels decreasing post-SCT. However, after SCT, iFGF-23 levels slightly increased in all patients with normal baseline levels (Fig.2C). Additionally, 7/10 patients had reduced osteocalcin levels (bone formation) before SCT, though this did not result in abnormal bone mineral density (BMD) (Fig.2D, TableS1). Given that bone mineralization is impaired in MDS [3], we also analyzed albumin-adjusted calcium, phosphate, and bone-specific alkaline phosphatase (BSAP). Calcium levels were reduced in 2/5 patients with elevated cFGF-23 and normalized after SCT (Fig.2E). All patients with normal cFGF-23 had calcium levels within the reference range, with only one showing reduced levels of phosphate, which were corrected by the SCT. Whereas 3/5 patients with high cFGF-23 had mild to moderate hypophosphatemia before SCT, only one remained hypophosphatemic after SCT (Fig.2F). In line with the increase of serum phosphate, BSAP levels, the major regulator of bone mineralization, also increased after SCT with high cFGF-23 (determined in 3/5 patients only, Fig.S2E). In addition, we analyzed 10 BM plasma samples regarding cFGF-23 and iFGF-23 levels in a separate set of patients with MDS (4 women, 6 men; median age: 57 years; TableS2). Since the samples were collected relatively shortly after SCT (range: 28 months), it is not surprising that the number of red blood cells was equal or decreased after SCT in 4/9 patients (data from one patient are not evaluable) compared to the basal levels (Fig.2G). In line with our previous observations, before SCT 5/10 patients had elevated cFGF-23 levels, which normalized after SCT. In patients with normal baseline cFGF-23, levels were either slightly increased (1/5 patients) or decreased (2/5) after SCT (Fig.2H). Before SCT, all patients had normal iFGF-23 levels. The SCT led to an increase in 6/10 patients and a decrease in 4/10 patients independently of the basal iFGF-23 levels (Fig.2I). Overall, the regulation of cFGF-23 in blood and BM plasma samples from patients with MDS after SCT suggests that BM cells are a source for cFGF-23 in MDS. This is supported by the transplantation of NHD13 BM cells, which causes the increase of cFGF-23 levels leading to impaired erythropoiesis and bone mineralization. Only erythroid precursors of NHD13 mice show a high Fgf23 expression, but myeloid cells and megakaryocytes do not (Fig.S1C, D). The question remains why and how cFGF-23 levels are increased in MDS. The expression of Galnt3 and Fam20c, which stabilize or mark FGF-23 for cleavage [6, 7], was normal in NHD13 erythroid precursors (Fig.S1E, F), indicating that these cells do not directly contribute to the increased cleavage of erythroid-derived FGF-23. Therefore, other signals or cells within the bone microenvironment or beyond may participate in this regulation. In line with this, it has been shown that FGF-23 production/cleavage can be triggered by erythropoietin, iron deficiency, anemia, and inflammation [8,9,10], factors that also play a role in MDS [11, 12]. While iron serum levels are unchanged in NHD13 mice, erythropoietin is upregulated. Since erythropoietin can affect FGF-23 production/cleavage in WT erythroid cells [8], this may be a possible regulator also in NHD13 mice. The whole inflammatory status of NHD13 mice has not been described yet, suggesting that inflammation and/or anemia might be drivers of cFGF-23 in NHD13 mice as well. The production of cFGF-23 is increased by inflammation, inhibits hepcidin induction in the liver, and increases iron bioavailability independent of the functions of iFGF-23 [10]. This scenario may hold true for MDS as it is also characterized by inflammation (and anemia) and may require high levels of cFGF-23 to provide enough iron for erythropoiesis. In our human cohorts, not all patients with MDS showed elevated cFGF-23 levels, and not all patients with elevated cFGF-23 showed dysregulations of iron or inflammation (TableS1). All patients with elevated cFGF-23 however did have anemia. MDS is a heterogeneous group of disorders. As NHD13 mice mimic a severe form of MDS with a high percentage of blasts in the bone marrow and a high propensity to transformation towards acute leukemia [13], we included patients with intermediate to very high-risk MDS in our cohorts and indicated their mutations. Analyzing the mutational landscape in patients with MDS might further allow assumptions on the underlying mechanisms leading to increased cFGF-23 levels. Mutations like TET2, DNMT3A, ASXL1, RUNX1, SF3B1, and SRSF2 are linked to increased responses to inflammatory stimuli [12, 14], and Tet2 or Dnmt3a deficiency causes bone loss in mice due to increased osteoclastogenesis [15]. In our blood plasma cohort, 4/5 patients with elevated cFGF-23 carried a mutation in at least one of these genes. However, 2/5 patients with normal cFGF-23 also had these mutations, but they received the MDS diagnosis a month earlier only. It is conceivable that the cFGF-23 levels increase after some time. Future research is needed to determine whether any of these mutations contribute to high cFGF-23 levels. In summary, we show that the high serum cFGF-23 levels in MDS originate from the BM and that BM transplantation/SCT can reduce cFGF-23 levels and its associated negative effects on erythropoiesis and bone mineralization. Future studies need to validate these findings in humans and address why cFGF-23 levels are increased in MDS.

The hematological and plasma parameters of patients with MDS were analyzed before and after allogeneic stem cell transplantation (SCT) in blood (AF) and bone marrow samples (GI). A, G The number of red blood cells was determined by the Sysmex XN-100 (Sysmex, Norderstedt, Germany). B, H C-terminal fibroblast growth factor (FGF)-23, (C, I) intact FGF-23, as well as (D) osteocalcin, were determined in plasma samples and in serum (E) albumin-adjusted calcium levels, as well as (F) phosphate levels, were measured by ELISA. n=10 except (G) n=9. The grey boxes in the graphs mark the reference range of healthy individuals. In all graphs, each dot represents a patient with MDS, and the values from the same patient are connected by a line (normal C-terminal FGF-23 before SCT, n=5) or dotted line (high C-terminal FGF-23 before SCT, n=5).

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Bone marrow transplantation reduces FGF-23 levels and restores bone formation in myelodysplastic neoplasms ... - Nature.com

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Authors of a recent review provide updates on stem cell transplants for myelofibrosis, with an emphasis on managing graft versus host disease and relapse.

Due to new transplant approaches, allogeneic hematopoietic stem cell transplant (HSCT) is now perceived as a safer therapeutic option in patients with myelofibrosis, even among older patients. Authors of a review published in the American Journal of Hematology emphasized the crucial role of early consideration and implementation of HSCT in improving clinical outcomes in this patient population.

Despite the approval of new therapies and various other exciting non-transplant treatments in development, allogeneic HSCT remains at present the only curative therapy for patients with myelofibrosis, wrote coauthors Haris Ali, MD, and Andrea Bacigalupo, MD.

The challenges associated with treating myelofibrosis include transplant-related mortality and the risk for relapse after HSCT. The authors aimed to provide a comprehensive review of current clinical data, new transplant platforms, and clinical updates, which can enhance patient outcomes.

The number of patients undergoing an allogeneic HSCT annually is steadily increasing, Dr. Ali and Dr. Bacigalupo wrote. This reflects the fact that HSCT has become safer with the reduction in non-relapse mortality over the years, making the choice of an HSCT more attractive among hematologists caring for [patients with myeloproliferative neoplasms].

Prior to HSCT, clinicians should conduct an in-depth assessment of organ functions, including cardiac, pulmonary, hepatic, and renal functions, as established by their institutions predefined criteria. This evaluation ensures that patients can withstand the possible physiological stresses of the transplant process, such as toxicity of the conditioning regimen, increased risk of infection, graft versus host disease (GVHD), and cytopenia. Patients should also undergo a detailed psychosocial assessment, which is an integral component of this process.

Following a thorough physical examination, we need to assess whether the patients disease justifies the risk from an allogeneic HSCT. Several prognostic scoring systems have been developed over the past years to identify patients who are likely to progress and are therefore at higher risk of morbidity and mortality, the authors explained.

The dynamic international prognostic scoring system is the most widely used prognostic tool for patients with myelofibrosis. Clinicians should account for patient age, as there are limited outcomes data regarding HSCT in patients with myelofibrosis who are aged 70 years or older.

The review offered information about approaches to managing splenomegaly and pretransplant treatment, recommended conditioning regimens, post-transplant outcome prediction models, recommendations for sourcing stem cells (eg, bone marrow, peripheral blood, cord blood), and criteria for selecting stem cell donors.

The authors provided protocol recommendations for preventing GVHD, managing patients with blast and accelerated phase myelofibrosis, and monitoring for disease markers. They also recommended monitoring driver mutations and early clinical intervention with cellular therapy to treat relapse. They also provided guidance for cases of hematologic reconstitution and graft failure.

The treatment is different according to the degree of donor chimerism: in patients who show mixed donor or only host-derived cells, the graft has failed completely, and the only solution is an early second transplant. On the other hand, if complete donor chimerism is present, then a boost of CD34 positive cells from the same donor, without conditioning regimen, can rescue over 70% of patients, Dr. Ali and Dr. Bacigalupo explained.

Myelofibrosis is a nuanced disease that often bears a significant transfusion burden and an unfavorable marrow environment, and early selection of patients for HSCT is critical to enhancing transplant outcomes.

HSCT in myelofibrosis is becoming safer due to new transplant strategies and is even offered in older patients. Early consideration of HSCT in patients with myelofibrosis is the key to the success of the transplant, Dr. Ali and Dr. Bacigalupo concluded.

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Allogeneic HSCT for Myelofibrosis: What to Know as More Patients Receive Treatment - Physician's Weekly

Today is World Sickle Cell Disease Day. The international awareness day is observed annually to increase public knowledge and an understanding of sickle cell disease and the challenges experienced by patients, their families, and caregivers. According to the CDC, Sickle cell disease (SCD) affects about 100,000 people in the United States; more than 90% are non-Hispanic Black or African Americans. The estimated life expectancy of those with SCD in the United States is more than 20 years shorter than the average expected. Sickle cell disease is an inherited blood disorder that affects red blood cells. People with sickle cell disease have red blood cells that contain mostly hemoglobin S, an abnormal type of hemoglobin.

Sometimes, these red blood cells become sickle-shaped (crescent-shaped) and have difficulty passing through small blood vessels. When sickle-shaped cells block small blood vessels, less blood can reach that body part. The tissue that does not receive normal blood flow eventually becomes damaged. However, the FDA approved a new sickle cell disease treatment in December 2023. The treatment is called Casgevy, the first medicine approved in the United States that uses CRISPR, a gene editing tool from Vertex Pharmaceuticals and CRISPR Therapeutics. In May 2024, a 12-year-old Black boy, Kendric Cromer, who suffered debilitating pain because of sickle cell disease, became the first patient in the United States to undergo a newly approved gene therapy.

Sickle cell disease has no specific age and affects children like Cali Cole, who was born with the disease and was miraculously cured at four years old, thanks to the help of her younger sister, who is now four. Kendra Cole shared with ESSENCE that her daughter Cali was born with sickle cell disease and received a bone marrow transplant on April 1, 2021, at four years old, curing her of sickle cell disease, thanks to a stem cell donation from her 18-month-old sister Reign (who we had through a year-long process of in-vitro fertilization). The family of five, Kendra, her husband, Lord Cole, and her three children (Cali, Reign, and Valor), bonded to brave through a timeline of medical events relating to sickle cell disease. In 2016, Kendra and Lord began family planning, knowing they wanted to grow their family. Through family planning, they decided to participate in genetic testing, where Kendra learned she had sickle cell trait.

In 2017, their first child, Cali, was born, and the familys medical team at Lurie Childrens Hospital in Chicago, Illinois, informed them that Cali had sickle cell disease, which was determined through newborn screening. From 2017-2021, Cali experienced the following complications due to sickle cell include: Splenic sequestration, Multiple pain crises, Dactylitis, Acute chest syndrome, Extreme constipation, Kidney damage, and Abnormal TCD brain scan results. At the end of 2017, the Cole family feverishly checked the Be the Match bone marrow registry for a potential match and did not find one, so they decided to try another child via IVF to see if it could be a bone marrow match. In 2018, Kendra began the IVF process again, and Reign was born in 2019. In 2021, the Cole family decided to move forward with the bone marrow transplant via stem cell donation of Reign. While Reign and Valor dont have sickle cell disease, they are susceptible to the trait.

Although now Cali is three years post-transplant with no complications and is living a happy, healthy life, sickle cell-free, her family remembers the toll sickle cell disease had on all of them. We spoke with Kendra to understand sickle cell diseases impact on her, her husband, and her children.

ESSENCE: Can you speak to your experience as a caregiver?

Kendra Cole: There were so many moments where there were high highs and lows. Any person who any parent who has a child, you know, they love them with every ounce of your being. At the same time, I felt immense guilt for not knowing my trait status. I often thought to myself, how could I have decided to bring a child into the world and have her experience so much pain early on in her life? I think there were many times throughout those first four years of her life that I felt like I was almost operating in survival mode a little bit. I wouldnt allow myself to be fully vulnerable with my daughter as her mother because I genuinely was just so afraid. But there were so many hospital days where I had to put on a brave face, be calm, and make these tough decisions within an emotionally charged atmosphere.

How can we be more of sickle cell disease in our community?

Sickle cell disease is an inherited blood disorder, so its not something that you can see. And pain is often subjective, right? So its painful to one person and may or may not be that painful to someone else.

Can you speak to the importance of Gene therapy?

Ive been excited about many new developments, specifically gene therapy. Gene therapy is a great advancement in sickle cell disease care and curative options, and there just hasnt been much movement on that in years.

How are you continuing to spread awareness?

Im still active in my local Sickle Cell Disease Association of Illinois chapter, whether through the parent group or our annual awareness walk. Ive also been in contact with several parents whose children want to undergo the bone marrow transplant process. Ive connected with many families and just offered them our story, support, and checking in with them.

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Life After Sickle Cell: A Seven-Year-Old Was Cured Of The Disease Thanks To Her Younger Sister - Essence

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Hematopoietic stem cell transplantation (HSCT) Market Future Growth Trends, Upcoming Opportunities and ... - openPR

"General Hospital" star John J. York got emotional while recounting his long cancer battle.

York, who announced his hiatus from the hit soap opera in September, was a guest on "Good Morning America" and explained that a number of people signed up to donate bone marrow after he announced his cancer diagnosis.

"Everybody has been very welcoming, very supportive," York said before beginning to cry. "And here I go already right off the top cause I cant tell you how nice its been, the support that Ive gotten."

'GENERAL HOSPITAL' ACTOR JOHNNY WACTOR'S KILLER AT LARGE, LAPD SHARES NEW DETAILS ABOUT THREE SUSPECTS

After a routine check-up in December 2022, York was diagnosed with two types of blood and bone marrow cancer: myelodysplastic syndrome and smoldering multiple myeloma.

According to the Mayo Clinic, myelodysplastic syndrome is "a group of disorders caused by blood cells that are poorly formed or don't work properly. Myelodysplastic syndromes result from something amiss in the spongy material inside your bones where blood cells are made (bone marrow)."

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The Mayo Clinic describes smoldering multiple myeloma as a form of multiple myeloma that does not always cause symptoms, explaining "If the myeloma is at an early stage and is growing slowly, you might have regular checkups to monitor the cancer."

"I made the announcement and it has helped. And so many people have joined the registry, just to help to save someone's life," York said, taking a pause in the middle of the statement as he continued to get emotional.

Due to both of York's diagnoses, he required a bone marrow transplant.

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The actor had to undergo seven days of chemotherapy at Vanderbilt University in Tennessee before he was allowed to get on a flight to Los Angeles to film "General Hospital." His first episode back will air on June 19.

After York was told he would have "3-5 years" if he did not undergo treatment, he decided to go the most "aggressive" route by getting a bone marrow transplant and chemotherapy.

"My philosophy was always, One day at a time, lets just get through today,'" he said. "I made the announcement, and it has helped and so many people have joined the registry just to help save someones life."

It took some time for York to find a stem cell donor. He recalled on "Good Morning America" the moment he found a donor.

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"She said we found an exact match and I just couldnt talk," York said. "Its just a little bag of blood and fluid, and they put it in my body, 40 minutes later, and now Im this person."

York explained that his cells are "now fighting each other and battling each other and getting to know each other."

"And here we are, back to work," he added. John has appeared on "General Hospital" since 1991.

York's hiatus from the show didn't feel very long to him, but rather felt like he "had a little break."

Original article source: 'General Hospital' star John J York returns to work after 'aggressive' cancer treatment

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'General Hospital' star John J York returns to work after 'aggressive' cancer treatment - Yahoo Entertainment

Study design

A dual-center, retrospective study of patients undergoing HCT for SAA was conducted at Vanderbilt University Medical Center (VUMC) and the associated Veterans Affairs hospital, Tennessee Valley Healthcare System (TVHS). The VUMC and TVHS Institutional Review Board approved the study. Patients with a SAA diagnosis who underwent first allogeneic HCT using FCR conditioning regimen at VUMC or TVHS between January 2016 and May 2022 were included in the study. Patients were excluded if they were younger than 18 or had not completed all planned treatments at the time of data collection.

All patients received conditioning per established protocol as determined by degree of HLA-matching with their designated donor (Fig.1). Patients received PBSC or BM grafts per treating physicians discretion with allogeneic HCT performed on day 0. In patients with matched related, matched unrelated, or 1-allele mismatched donors, fludarabine (30mg/m2) was given intravenously for four days (7 to 4, i.e., 7 to 4 days before transplantation) in combination with cyclophosphamide (750mg/m2) given intravenously for three days (6 to 4) and anti-thymocyte globulin (rabbit) (3.75mg/kg) for two days (2 and 1). They were also given rituximab (375mg/m2) on days 13, 7, +1, and +8.

Doses and timing of each agent in FCR conditioning regimens for patients undergoing HCT for SAA with matched related, matched unrelated, or 1-allele mismatch donor (a) or haploidentical donor (b). Time in days is represented along the horizontal axis progressing from left to right, with day of transplantation depicted as day 0.

Patients who underwent HCT from a haploidentical donor received fludarabine (30mg/m2) intravenously for five days (6 to 2) and cyclophosphamide (14.5mg/kg) for two days (6 to 5). They also received rituximab (200mg/m2) on day +5. All patients received total body irradiation at a dose of 200cGy on day 0 for those with matched related, unrelated, or 1-allele mismatched donors, or on day 1 for those with haploidentical donors.

Prophylaxis for GVHD in patients with matched related, matched unrelated, or 1-allele mismatch donors consisted of tacrolimus starting on day 3 and methotrexate, 5mg/m2 intravenously, on days +1, +3, and +6 after transplantation. Patients with haploidentical donors received standard post-transplant cyclophosphamide (50mg/kg on days +3 and +4), and tacrolimus and mycophenolate mofetil starting on day +5. Tacrolimus levels were adjusted to a goal range of 515ng/mL per institutional standard, and administered for 180 days, at which point a taper was initiated provided absence of GVHD. Mycophenolate mofetil was administered until day +35 in patients with haploidentical donors.

The primary outcome of interest was GVHD-free/relapse-free survival. A patient was considered to have an event if they experienced moderate or severe GVHD (including both acute GVHD [aGVHD] and cGVHD), relapse, or death. If a patient experienced multiple events, the earliest event date was used as the time to event (e.g., if a patient had a diagnosis of both aGVHD and cGVHD, the earliest date of diagnosis was used). If a patient did not experience an event until the end of follow-up time (i.e., the last date the patient was seen in the clinic or lost to follow-up [unable to contact, transitioned care to another city, etc.]), it was censored. Acute and chronic GVHD were graded according to Glucksburg and 2014 National Institutes of Health consensus criteria, respectively [17, 18]. Secondary outcomes included time to engraftment, incidence of graft failure, incidence of GVHD, rate of viral reactivation, post-HCT disease status, and number of inpatient hospital days.

Descriptive statistics were used to summarize the patient characteristics. Medians and interquartile ranges (IQRs) were used for continuous variables, while frequencies and percentages were used for categorical variables. Differences in patient characteristics were tested for using Wilcoxon rank sum tests for continuous variables and chi-square tests for categorical variables. Probability of GRFS over time was estimated using the Kaplan-Meier estimation method.

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Efficacy and safety of outpatient fludarabine, cyclophosphamide, and rituximab based allogeneic hematopoietic cell ... - Nature.com

Key Takeaways

CAR-T cell therapy doesnt increase a persons risk of secondary cancers, researchers reportThe risk of a secondary cancer is slightly more than 6%, about the same as stem cell transplantation to treat blood cancersOther factors appear to be involved in secondary cancers

THURSDAY, June 13, 2024 (HealthDay News) CAR-T cell therapy to treat blood cancers is safer than previously thought, with little risk that the immunotherapy will create secondary cancers, a new study finds.

The U.S. Food and Drug Administration issued a warning in November 2023 about a risk of secondary cancers that might be associated with CAR-T cell therapy.

But a study of more than 700 patients treated at Stanford University found that the risk was just over 6% in the three years after a cancer patient received CAR-T cell immunotherapy, researchers reported June 13 in the New England Journal of Medicine.

That risk is roughly similar to that of patients who receive stem cell transplants rather than CAR-T cell therapy to treat their blood cancers, researchers said.

These are lifesaving therapies that come with a very low risk of secondary cancers. The challenge lies in how to predict which patients are at higher risk, and why, said researcher Dr. Ash Alizadeh, a professor of medicine at Stanford.

In CAR-T cell therapy, immune cells called T-cells are harvested from a patient and genetically engineered to more efficiently seek out and kill cancer cells.

This therapy typically is used to treat blood cancers like leukemia, lymphoma and multiple myeloma, according to the American Cancer Society.

But one concern is that if the genetic engineering is imprecise, the T-cells meant to attack a persons cancer might instead become cancerous themselves.

To see whether this risk is real, the research team analyzed data drawn from Stanford Medicines large bank of tissue and blood samples from people receiving CAR-T cell therapy.

They found no evidence that the T-cells responsible for some patients secondary cancers were the T-cells that had been engineered for CAR-T cell therapy. The T-cells were distinct on both genetic and molecular levels.

But in one patient who rapidly developed and died from a T-cell lymphoma, researchers found a clue that could explain why secondary cancers sometimes happen.

Both sets of T-cells in that patient the CAR-T cells and the T-cells responsible for the secondary cancer had been infected with a virus known to play a role in cancer development. The patient also had a history of autoimmune disease prior to a cancer diagnosis.

We compared protein levels, RNA sequences and DNA from single cells across multiple tissues and time points to determine that the therapy didnt introduce the lymphoma into this patient; instead it was already brewing in their body at very low levels, Alizadeh said in a Stanford news release.

This suggests that secondary cancers might be prompted by chemotherapy done prior to CAR-T cell therapy, which suppresses a persons immune response to such viruses, researchers said. They also might be due to some other side effect from the treatment, rather than genetic engineering gone wrong.

These results may help researchers focus on the immune suppression that can precede and often follows CAR-T cell therapy, said researcher Dr. David Miklos, chief of bone marrow transplantation and cellular therapy at Stanford Medicine.

More information

The American Cancer Society has more about CAR-T cell therapy.

SOURCE: Stanford University, news release, June 12, 2024

What This Means For You

People with blood cancers can receive CAR-T cell therapy with little fear of increased risk for secondary cancers, researchers say.

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Secondary Tumors After CAR-T Cancer Therapies Are Rare: Study | Fox 11 Tri Cities Fox 41 Yakima - FOX 11 and FOX 41

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Salute to saving a life: Local Air Force man answers the call for stem cell donation - Citrus County Chronicle

DADDY, can we play football?

Those are the most beautiful words in the world to Mo Hussain, 38, from Blackburn, because they mean his five-year-old son Eesa is having a good day.

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And to ensure more good days lie ahead, this devoted father is a man on a mission, seeking the stem cell match that will save his little boys life.

On New Years Day, Eesa felt sick and looked really pale, Mo says. Concerned, we took him to A&E.

Its every parents worst nightmare. A few hours later their son was being transferred by ambulance to Royal Manchester Childrens Hospital.

Normal levels of haemoglobin a protein which transports oxygen around the body are 120-150g/l. Eesas was 42g/l due to dangerously low red blood cell levels.

I want to go home and play with my dinosaurs, Eesa cried. Mos heart broke.

Mo cuddled Eesa as he had a general anaesthetic for a bone marrow biopsy.

That night, the whole family Mo, his wife and two-year-old son Ali crammed into Eesas cubicle on ward 86 to sleep. We needed to be together, Mo says.

The biopsy showed Eesa had a rare, life-threatening condition called aplastic anaemia, meaning his bone marrow and stem cells dont produce enough red and white blood cells and platelets.

The best cure is a bone marrow transplant from a matching donor.

While preparations were made to test the familys suitability, Eesa had a Hickman line fitted in his chest so doctors could administer medicines and take blood.

To make it less frightening, I bought some plastic tubing and stuck it to my chest too, says Mo.

Back home after a week in hospital, the family were on lockdown Eesa off school and Mo and his wife on leave from work.

We cant risk Eesa catching something his bodys weak immune system cant fight, Mo says.

Devastatingly, no one in Eesas family is a donor match for him.

But there is hope. Fifty years ago, Shirley Nolan was so determined to save her son Anthonys life that she set up the worlds first stem cell register.

Since 1974, the charity Anthony Nolan has helped bring about more than 26,500 transplants for people around the world.

If youre from a minority ethnic background, youre more likely to have a rare or completely unique tissue type.

Thats why theres a pressing need to recruit more people from diverse backgrounds to the register to help patients like Eesa find the lifesaving matches they need.

I had to educate our community, Mo says. The team at Anthony Nolan sent me swabs for people to wipe inside their mouths and envelopes to post them back.

And, in February, we set up our first registration stall at a football tournament.

Since then, Mo and his family and friends have visited mosques, universities and football stadiums including the Etihad, Turf Moor and Ewood Park 40 locations in all, adding 1,200 potential new donors to the register.

Sadly, Eesa is still waiting for his match and remains dependant on blood transfusions every three weeks.

I find patience in the words of the Quran saving one life is like saving the whole of humanity, says Mo.

Anthony Nolan shares its register across the world so the people we sign up could save lives in Bangladesh, Pakistan anywhere.

For now, Eesa has good days watching Arsenal and racing his police cars and bad. In April, he was hospitalised because his Hickman line became infected.

Hes the bravest five-year-old in Britain, Mo says. But we just want a normal childhood for him.

The greatest Fathers Day gift I could receive is a match for Eesa. So Im appealing to other dads log on to anthonynolan.org today.

You could save someone like my sons life.

Follow the My Name is Eesa campaign on Instagram at @mynameiseesa

Joining the stem cell register is easy. You must be aged between 16 and 30, as research shows younger donors offer better survival rates for patients.

Fill in a form at anthonynolan.org to receive a swab pack then take a sample and send it back.

Ken (above), 26, from Tower Hamlets, signed up to the register eight years ago at an Anthony Nolan stand handing out Krispy Kreme doughnuts.

And three years later he discovered he was a match for someone.

I was given G-CSF injections at home for four days, he says. G-CSF injections boost white cells and release stem cells into the bloodstream ready to collect.

They gave me minor headaches and muscle pain nothing more. On the fifth day I was in hospital, donating my stem cells and afterwards I was fine.

I hope that more people will join the stem cell register and help Anthony Nolan save the lives of people with blood cancer and blood disorders.

If a family member or friend was diagnosed with blood cancer, it would make such a difference to know that they have a match and a second chance at life.

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Are you under 30? Join the stem cell register and be part of a one million strong team of lifesavers. Sign up at anthonynolan.org

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Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced longer-term data for CASGEVY (exagamglogene autotemcel [exa-cel]) from global clinical trials in people with severe sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT). The results, presented at the annual European Hematology Association (EHA) Congress, confirm the transformative, consistent and durable clinical benefits of CASGEVY over time. CASGEVY is the first and only approved CRISPR-based gene-editing therapy.

The data being presented are from more than 100 patients (46 SCD; 56 TDT) treated with exa-cel in clinical trials, with the longest follow-up now extending more than 5 years. The efficacy results are consistent with the previously reported primary and key secondary endpoints analyses from these exa-cel studies and continue to demonstrate transformative clinical benefit with durable and stable levels of fetal hemoglobin (HbF) and allelic editing.

The transformative benefit seen in patients with sickle cell disease in the trial is impressive given the significant and cumulative burden of disease faced by people living with this blood disorder, said Haydar Frangoul, M.D., M.S., Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute and HCA Healthcares TriStar Centennial Childrens Hospital. I am eager to offer this therapy and the opportunity of a potential functional cure to my eligible patients.

The comprehensive data set presented today for adult and adolescent TDT patients adds to the growing body of evidence for CASGEVY, and it is important to now ensure the availability of this innovative treatment to patients in the real world as soon as possible, said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the Catholic University of the Sacred Heart of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Ges Childrens Hospital. With the longest follow up now more than five years, alongside stable editing and sustained fetal hemoglobin levels, I have conviction in the durable benefit to the patients treated with CASGEVY.

New data presented from CASGEVY pivotal trials

In both SCD and TDT patients, edited levels of BCL11A alleles were stable over time in bone marrow and peripheral blood indicating successful editing in the long-term hematopoietic stem cells. All patients engrafted neutrophils and platelets after exa-cel infusion. The safety profile of exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant.

These longer-term data for CASGEVY from the CLIMB clinical trials will be shared as outlined below:

Vertex will also share five health economics abstracts at the EHA Congress.

About Sickle Cell Disease (SCD)

SCD is a debilitating, progressive, life shortening genetic disease. SCD patients report health-related quality of life scores well below the general population and significant health care resource utilization. SCD affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or sickled red blood cells. The clinical hallmark of SCD is vaso-occlusive crises (VOCs), which are caused by blockages of blood vessels by sickled red blood cells and result in severe and debilitating pain that can happen anywhere in the body at any time. SCD requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with SCD is around 40 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with SCD because of the lack of available donors.

About Transfusion-Dependent Beta Thalassemia (TDT)

TDT is a serious, life-threatening genetic disease. TDT patients report health-related quality of life scores below the general population and significant health care resource utilization. TDT requires frequent blood transfusions and iron chelation therapy throughout a persons life. Due to anemia, patients living with TDT may experience fatigue and shortness of breath, and infants may develop failure to thrive, jaundice and feeding problems. Complications of TDT can also include an enlarged spleen, liver and/or heart, misshapen bones and delayed puberty. TDT requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with TDT is 50-55 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with TDT because of the lack of available donors.

About CASGEVY (exagamglogene autotemcel [exa-cel])

CASGEVY is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patients own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth.

CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT.

CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients.

About the CLIMB Studies

The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and CLIMB-121, are designed to assess the safety and efficacy of a single dose of CASGEVY in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after CASGEVY infusion. Each patient will be asked to participate in the ongoing long-term, open-label trial, CLIMB-131. CLIMB-131 is designed to evaluate the safety and efficacy of CASGEVY in patients who received CASGEVY in other CLIMB studies. The trial is designed to follow patients for up to 15 years after CASGEVY infusion.

U.S. INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR CASGEVY (exagamglogene autotemcel)

WHAT IS CASGEVY?

CASGEVY is a one-time therapy used to treat people aged 12 years and older with:

CASGEVY is made specifically for each patient, using the patients own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with beta thalassemia.

IMPORTANT SAFETY INFORMATION

What is the most important information I should know about CASGEVY?

After treatment with CASGEVY, you will have fewer blood cells for a while until CASGEVY takes hold (engrafts) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels.

You may experience side effects associated with other medicines administered as part of the treatment regimen for CASGEVY. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects.

How will I receive CASGEVY?

Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. Its important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment.

After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment.

STEP 1: Before CASGEVY treatment, a doctor will give you mobilization medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis). This entire process may happen more than once. Each time, it can take up to one week.

During this step rescue cells are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold (engraft) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY.

STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider.

STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the infusion with CASGEVY.

STEP 4: One or more vials of CASGEVY will be given into a vein (intravenous infusion) over a short period of time.

After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home.

What should I avoid after receiving CASGEVY?

What are the possible or reasonably likely side effects of CASGEVY?

The most common side effects of CASGEVY include:

Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms:

These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of CASGEVY

Talk to your healthcare provider about any health concerns.

Please see full Prescribing Information including Patient Information for CASGEVY.

About Vertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia and continues to advance clinical and research programs in these diseases. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including acute and neuropathic pain, APOL1-mediated kidney disease, IgA nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes, myotonic dystrophy type 1 and alpha-1 antitrypsin deficiency.

Vertex was founded in 1989 and has its global headquarters in Boston, with international headquarters in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia, Latin America and the Middle East. Vertex is consistently recognized as one of the industry's top places to work, including 14 consecutive years on Science magazine's Top Employers list and one of Fortunes 100 Best Companies to Work For. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on LinkedIn , YouTube and Twitter/X .

(VRTX-GEN)

Vertex Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the statements by Haydar Frangoul, M.D., M.S., and Franco Locatelli, M.D., Ph.D., in this press release, and statements regarding our expectations for and the anticipated benefits of CASGEVY, our plans to share longer-term data for CASGEVY from the CLIMB clinical trials and to share health economics abstracts at the EHA Congress, and our plans for and design of the CLIMB studies. While we believe the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy, and other reasons, and other risks listed under the heading Risk Factors in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com . You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

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Vertex Pharmaceuticals Incorporated

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Media: mediainfo@vrtx.com or International: +44 20 3204 5275 or U.S.: 617-341-6992 or Heather Nichols: +1 617-839-3607

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Vertex Presents Positive Long-Term Data On CASGEVY (exagamglogene autotemcel) at the 2024 Annual European ... - Agenzia ANSA

Patients

Patients eligible for the study were aged 12 years, weighed 30kg and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 if aged 18 years34 and Karnofsky or Lansky PS60% if aged 16 years or 12 to <16 years35, respectively (see Supplementary Tables 5 and 6 for details of PS scoring systems). All patients were to receive either peripheral blood or bone marrow allo-HSCT for hematologic malignancy from unrelated donors who were 8 of 8 or 7 of 8 human leukocyte antigen (HLA)-matched (a single allele mismatch at HLA-A, HLA-B and HLA-C, and HLA-DRB1 was permitted). A total of 441 patients were screened for eligibility. After screening, 343 patients were randomly assigned 1:1 to receive vedolizumab (174 patients) or placebo (169 patients) treatment. Randomization was stratified by age (patients aged 18 years or aged 12 to <18 years); HLA match (8 of 8 versus 7 of 8); conditioning regimen intensity (myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC)); and anti-thymocyte globulin (ATG) use (with versus without ATG). Patients received either vedolizumab 300mg or placebo intravenously on day 1 and days +13, +41, +69, +97, +125 and +153 after allo-HSCT in addition to standard GVHD prophylaxis (CNI plus methotrexate or mycophenolate mofetil). Nine patients did not receive study treatment, five were randomized to vedolizumab and four were randomized to placebo treatment.

Of 334 patients who received 1 dose of study treatment (analyzed for safety study end points), 333 also received allo-HSCT (analyzed for efficacy study end points), 168 in the vedolizumab group and 165 in the placebo group. For patients discontinuing the study, reasons for discontinuation included death (26 out of 57 patients in the vedolizumab group and 34 out of 71 in the placebo group), withdrawal by the patient (16 versus 18) and adverse events (AEs; 6 versus 5) (Fig. 1). Median (range) exposure to treatment was 40.0 (18.142.1) weeks for vedolizumab and 39.7 (18.142.3) weeks for placebo. In the vedolizumab group, patients received a mean (s.d.) of 5.4 (2.1) and median (range) 7.0 (17) treatment doses; 52.7% of patients in the vedolizumab group received all seven doses. A mean (s.d.) of 5.1 (2.3) and median (range) 7.0 (17) doses were received in the placebo group; 50.9% of patients in this group received all seven doses. Patient numbers were reduced to 60% of the planned sample size of 558 because of early enrollment termination owing to the impact of COVID-19 on recruitment. Consequently, more patients (n=137, 41.1%) received ATG at baseline than the 25% planned.

Discontinuation of the study refers to all patients who discontinued before the end of the long-term follow-up safety survey period of the study, 6 months after the last dose of study treatment. Withdrawn by physician is noted as reason other. Patients included in the analysis for efficacy end points per protocol were those who received 1 dose of study treatment and also received allo-HSCT. One patient was randomized to receive vedolizumab but did not receive allo-HSCT; per protocol, this patient was not included in the analysis of efficacy end points but was included in the analysis of safety end points.

Patient and transplant characteristics were balanced between treatment groups (Table 1 and Extended Data Table 1). The median age was 55.0 years (range, 1674 years; 1 aged <18 years) and 62.8% were male. The most frequent underlying malignancies were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoid leukemia (ALL). The conditioning regimen intensity was either MAC (52.4% in the vedolizumab group versus 53.9% in the placebo group) or RIC. GVHD prophylaxis (with or without ATG) was tacrolimus (TAC)+methotrexate (MTX; 42.3% versus 50.3%) or TAC+mycophenolate mofetil (MMF; 3.0% versus 3.0%); cyclosporine (CYS)+MTX (30.4% versus 23.0%) or CYS+MMF (14.3% versus 12.1%). The proportion of patients who received ATG prophylaxis was balanced between treatment groups: 42.3% (n=71) in the vedolizumab group versus 40.0% (n=66) in the placebo group; 57.7% versus 60.0% did not receive ATG.

Neutrophil engraftment occurred in 165 patients in the vedolizumab treatment group and 160 patients in the placebo group. The median (range) time to neutrophil engraftment was 16.0 (835) days in the vedolizumab group and 15.0 (831) days in the placebo group. Platelet engraftment occurred in 159 patients in the vedolizumab group and 148 patients in the placebo group. The median (range) time to platelet engraftment was 18.0 (1136) days in the vedolizumab group and 17.0 (0233) days in the placebo group.

The primary study end point was lower-GI aGVHD-free survival by day +180 after allo-HSCT. There were 24 (14.3%) patients in the vedolizumab group with an event of lower-GI aGVHD or death by day +180 after allo-HSCT compared to 47 (28.5%) patients in the placebo group (Fig. 2a). The frequency of lower-GI aGVHD by maximum clinical stage (see Supplementary Table 1 for a description of clinical staging of aGVHD9) is shown in Fig. 2b for each treatment group, with four cases of stage 24 lower-GI aGVHD in the vedolizumab group compared to 14 cases observed in those who received placebo. The KaplanMeier (KM) estimate for lower-GI aGVHD-free survival by day +180 was 85.5% (95% confidence interval (CI) 79.290.1) for the vedolizumab group and 70.9% (63.277.2) for the placebo group (Fig. 2c). The risk of a lower-GI aGVHD event or death by day +180 after allo-HSCT was 55% less in the vedolizumab group compared to the placebo group (hazard ratio (HR) 0.45, 95% CI 0.270.73; P<0.001). Results were consistent for sensitivity analyses of the primary end point (Table 2), including events occurring within a 7-day time frame at day +187 after allo-HSCT, stratified log-rank tests by randomization stratification factors, analysis with corrected stratification information, competing risk analysis and an analysis excluding aGVHD events graded stage 0 or unknown. By day +180 after allo-HSCT, 23 patients (13.7%) in the vedolizumab group versus 43 (26.1%) in the placebo group had an event of death or lower-GI aGVHD (when aGVHD events graded stage 0 or unknown were excluded) (HR 0.47, 95% CI 0.280.78; P=0.0029). In subgroup analyses of the primary end point (Fig. 2d and Extended Data Fig. 1), HRs consistently favored vedolizumab over placebo regardless of HLA match, conditioning regimen intensity, use of ATG or stem-cell source (bone marrow or peripheral blood). The overall incidence of upper-GI aGVHD, skin aGVHD and aGVHD in the liver by day +180 after allo-HSCT was similar between treatment groups (Supplementary Table 7).

Analysis included all randomized patients who received 1 dose of study treatment and received allo-HSCT. All statistical tests were two-sided. a, Graph shows number and proportion of patients with a lower-GI aGVHD event or death; censored for patients who had not had the lower-GI aGVHD event or died or had the event after a prespecified time, for example, last contact or day +180 after allo-HSCT, whichever occurred first. If a patient had a lower-GI aGVHD event and died due to any cause, including lower-GI aGVHD, the time to event was derived as the time to the first qualifying event (lower-GI aGVHD event). b, Frequency of lower-GI aGVHD by maximum clinical stages 04 by day +180 after allo-HSCT for patients in vedolizumab and placebo treatment groups and also the corresponding frequency of skin aGVHD and liver aGVHD in these treatment groups by maximum clinical stages 04 by day +180 after allo-HSCT. CI was based on the ClopperPearson method. c, KM estimate for the primary study end point lower-GI aGVHD-free survival from first study treatment (day 1) to lower-GI aGVHD event or death due to any cause. Red line shows the vedolizumab group; blue line shows the placebo group; open circles indicate censored patients. HR obtained via a Cox proportional hazards model with treatment group, stratified by randomization stratification factors: HLA match (7 of 8 or 8 of 8), conditioning regimen (MAC or RIC), ATG (with or without) and P value from a log-rank test (P=0.0009). d, Forest plot of prespecified subgroup analyses for the primary study end point of lower-GI aGVHD-free survival by day +180 after allo-HSCT: conditioning regimen MAC or RIC, with or without ATG, CNI TAC or CYS, HLA match, and stem cell source peripheral blood or bone marrow. HRs plotted with 95% CIs were obtained via a Cox proportional hazards model with treatment group stratified by randomization strata. Results for the remaining prespecified subgroup analyses are shown in Extended Data Fig. 1.

The KM estimates for the five key secondary end points analyzed at day +180 after allo-HSCT are shown in Fig. 3.

ae, KM estimates for the secondary efficacy end points. Analyses included all randomized patients who received 1 dose of study treatment and allo-HSCT. In the fixed-sequence hierarchical testing procedure, once 1 efficacy end point was not significant (P0.05), testing of subsequent end points was not performed. P values were obtained using a log-rank test unless otherwise stated. All statistical tests were two-sided. *P value is significant for vedolizumab versus placebo. HR and 95% CI values were obtained from a Cox proportional hazards model with treatment group stratified by randomization strata: HLA match (7 of 8 or 8 of 8), conditioning regimen (MAC or RIC) and ATG (with or without). Time to first documented lower-GI aGVHD, relapse of underlying malignancy or death from any cause. Sensitivity analysis, excluding lower-GI aGVHD events classified as clinical grade 0 or unknown. NRM was a competing risk in this competing risk sensitivity analysis; P value for comparison of vedolizumab with placebo was obtained by a Grays test. Time to first documented IBMTR grade CD aGVHD (any organ) or death from any cause. **Death and relapse were competing risks in this sensitivity analysis; an event was defined as IBMTR grade CD aGVHD (any organ) or death. P value was obtained by a Grays test. Death from first dose of study treatment without occurrence of a relapse. Relapse was a competing risk in this sensitivity analysis; NRM was the time from first study treatment to death without occurrence of a relapse; P value was obtained by a Grays test. Overall survival by day +180 was the analysis of the time from the first dose of study treatment to death from any cause. All deaths were defined as events in this analysis. Time to first documented IBMTR grade BD aGVHD (any organ) or death from any cause. Death and relapse were competing risks in this sensitivity analysis; an event was defined as IBMTR grade BD aGVHD (any organ) or death. P value was obtained by a Grays test.

There was a statistically significant difference favoring vedolizumab over placebo for lower-GI aGVHD-free and relapse of the underlying malignancy-free survival by day +180 after transplant. The KM estimated survival for this end point was 78.9% for the vedolizumab treatment group versus 65.4% for the placebo group. Events of lower-GI aGVHD, relapse or death for this end point occurred in 11, 18 and 6 patients, respectively from the vedolizumab group (total of 35, 20.8%) and 31, 13 and 12 (total of 56, 33.9%) in the placebo group (HR 0.56, 95% CI 0.370.86; P=0.0043). A statistically significant treatment difference favoring vedolizumab for this end point was also maintained after a sensitivity analysis excluding stage 0 and unknown lower-GI aGVHD events (HR 0.59, 95% CI 0.380.91; P=0.0130) (Fig. 3). The secondary end point of IBMTR grade CD aGVHD of any organ-free survival by day +180 (see Supplementary Table 3 for description of aGVHD severity grading using the IBMTR severity index), also demonstrated a statistical difference between vedolizumab and placebo treatment groups. The KM estimated survival for this end point was 78.9% for vedolizumab the treatment group versus 67.7% in the placebo group. Events of grade CD aGVHD of any organ or death counted for this end point occurred in 35 patients (20.8%) receiving vedolizumab versus 52 (31.5%) receiving placebo (HR 0.59, 95% CI 0.390.91; P=0.0204). In a competing risk analysis (death and relapse as competing risks), cumulative incidence of IBMTR grade CD aGVHD by day +180 was lower for the vedolizumab group (13.2%, 95% CI 8.618.8) than the placebo group (21.6%, 95% CI 15.628.2; P=0.0446) (Fig. 3). Secondary end point sensitivity analyses (Supplementary Table 8) and subgroup analyses (Extended Data Fig. 2) showed consistent results with decreased risk in the vedolizumab group compared to the placebo treatment group. The secondary end point of non-relapse mortality (NRM) by day +180 did not meet statistical significance, with 10 patients (6.0%) in the vedolizumab group and 19 (11.5%) in the placebo group (HR 0.48, 95% CI 0.221.04; P=0.0668) dying of non-relapse causes. Following the hierarchical statistical testing procedure, the subsequent fourth and fifth secondary end points were not tested for statistical significance. The KM estimate for the fourth secondary end point of overall survival was 89.7% for the vedolizumab treatment group and 84.4% in the placebo group. All-cause deaths by day +180 counted for this analysis occurred in 17 patients (10.1%) in the vedolizumab group and 25 (15.2%) in the placebo group (HR 0.63, 95% CI 0.341.17; P=0.1458). For the fifth secondary end point of IBMTR grade BD aGVHD of any organ-free survival by day +180, KM estimated survival was 66.4% for the vedolizumab treatment group and 52.3% in the placebo group. Grade BD aGVHD events in any organ counted for this end point occurred in 47 patients (28.0%) in the vedolizumab group and 64 (38.8%) in the placebo group with deaths also counted in 9 and 13 patients in the vedolizumab and placebo groups, respectively (HR 0.64, 95% CI 0.460.91; P=0.0105).

Results for the main exploratory end points at day +180 and day +365 after transplant are summarized (Extended Data Tables 3 and 4). The cumulative incidence of all chronic GVHD events by day +180 was 20.7% (95% CI 14.827.2) in the vedolizumab group versus 21.9% (95% CI 15.828.6) in the placebo group (death and relapse as competing risks; nominal P=0.7555). Chronic GVHD requiring systemic immunosuppression by day +180 occurred in three (1.8%) patients in the vedolizumab group (severity was moderate in two patients and severe in one) and four (2.4%) in the placebo group (one mild, two moderate and one patient had severe chronic GVHD) (Extended Data Table 3). KM estimates for GVHD (any organ)-free and relapse (of the underlying malignancy)-free survival by day +180 were 80.1% in the vedolizumab group and 69.7% in the placebo group; events for this end point occurred in 33 (19.6%) of patients in the vedolizumab group and 49 (29.7%) in the placebo group (HR 0.61, 95% CI 0.390.96; nominal P=0.0243). Events of clinical stage 24 lower-GI aGVHD or death by day +180 occurred in fewer patients in the vedolizumab group (19, 11.3%) than in the placebo group (33, 20.0%) (HR 0.52, 95% CI 0.290.91; nominal P=0.0222). KM estimates for clinical stage 24 lower-GI aGVHD-free survival were 88.5% and 79.5%, respectively. By day +180 grade 24 aGVHD-free survival (per MAGIC criteria10, see Supplementary Table 4) also seemed to favor vedolizumab over placebo; KM estimates were 74.1% for vedolizumab and 63.3% for placebo, with events occurring in 43 (25.6%) and 59 (35.8%) patients, respectively (HR 0.67, 95% CI 0.450.99; nominal P=0.0421). Frequency of lower-GI aGVHD by maximum MAGIC grade were also reported for each treatment group, with corresponding values for maximum MAGIC grade of skin and liver aGVHD (Extended Data Table 2).

Progression-free survival in vedolizumab and placebo treatment groups by day +180 were 83.1% (95% CI 76.588.0) versus 77.6% (95% CI 70.483.3), respectively. Cumulative incidence of all relapse and death events for time to relapse (of the underlying malignancy) by day +180 were similar across treatment groups 10.9% (95% CI 6.716.2) for vedolizumab versus 10.6% (95% CI 6.416.0) for placebo (death as a competing risk; nominal P=0.9090). By day +180, there was no significant difference in relapse of the underlying malignancy between treatment groups, occurring in 18 (10.7%) patients from the vedolizumab group and 17 (10.3%) from the placebo group (HR 1.32, 95% CI 0.513.40; nominal P=0.9821; Extended Data Table 3).

Consistent results were obtained for primary and secondary efficacy end points when these were assessed as exploratory study end points 1 year after allo-HSCT (Extended Data Table 4). By day +365 after allo-HSCT, 21.4% of patients in the vedolizumab group and 33.9% in the placebo group had an event of lower-GI aGVHD or death (HR 0.53, 95% CI 0.350.81; nominal P=0.0041). KM estimates for lower-GI aGVHD-free survival 1 year after transplant were 78.1% for vedolizumab and 65.1% for placebo. Events of IBMTR grade CD aGVHD of any organ or death by day +365 occurred in 47 (28.0%) of patients in the vedolizumab group and 59 (35.8%) of patients in the placebo group (HR 0.68, 95% CI 0.461.00; nominal P=0.0709). Death without relapse occurred in 15 patients (8.9%) in the vedolizumab group and 25 (15.2%) in the placebo group (HR 0.49, 95% CI 0.250.95; nominal P=0.0670). All-cause deaths by day +365 occurred in 28 patients (16.7%) in the vedolizumab group and 36 (21.8%) in the placebo group (HR 0.67, 95% CI 0.411.11; nominal P=0.1741). IBMTR grade BD aGVHD in any organ or death events occurred in 69 patients (41.1%) in the vedolizumab group and 82 (49.7%) in the placebo group (HR 0.71, 95% CI 0.520.99; nominal P=0.0534). Incidence of relapse of the underlying malignancy at day +365 was also comparable between treatment groups occurring in 19.6% of patients in the vedolizumab group versus 13.3% for placebo (HR 2.13, 95% CI 0.974.65; nominal P=0.2097; Extended Data Table 4).

The safety analyses included 334 patients (169 patients in the vedolizumab group and 165 in the placebo group) who received 1 dose of study treatment and were assessed up to 18 weeks after the last dose of study treatment. Median (range) treatment exposure was 280.0 (127295) days for the vedolizumab group (mean (s.d.) of 5.4 (2.05) doses) and 278.0 (127296) days for the placebo group (mean 5.1 (2.25) doses). AEs of grade 3 or higher occurred in 92.3% of patients who received vedolizumab and 89.1% who received placebo (Table 3); the most frequent AEs of grade 3 or higher were anemia (29.6% versus 31.5%); neutropenia (31.4% versus 29.7%); febrile neutropenia (43.8% versus 42.4%); stomatitis (27.2% versus 26.7%); and decreased platelet count (21.9% versus 24.8%). Serious AEs occurred in 120 patients (71.0%) who received vedolizumab and 114 (69.1%) who received placebo (Extended Data Table 5). AEs led to treatment discontinuation in 44 (26.0%) versus 51 patients (30.9%) (Extended Data Table 6).

Table 3 lists serious infections among other AEs (serious and non-serious) prespecified as being of special interest (AESIs) in the study. Occurrence of post-transplant lymphoproliferative disease and Clostridioides infections are also reported in Table 3. AESIs included cytomegalovirus (CMV) colitis, which was reported in one patient from each treatment group (0.6% of patients in vedolizumab group 0.6% in the placebo group). Overall, CMV reactivation was reported in 23.7% of patients in the vedolizumab group and 18.2% in the placebo group. Most of the CMV reactivation events were grade 1 to grade 2 and none was above grade 3. The proportions of patients with grade 3 CMV reactivation were similar in both treatment groups. CMV infections were analyzed in subgroups of patients who received ATG prophylaxis or not (Supplementary Table 9). For those receiving ATG, grade 3 CMV infections occurred in seven patients (4.1%) in the vedolizumab group and six patients (3.6%) in the placebo group and serious CMV infections in seven (4.1%) versus three patients (1.8%), respectively. For patients treated without ATG, the frequency of grade 3 CMV infections was numerically lower in vedolizumab-treated versus placebo-treated patients (1 (0.6%) versus 3 (1.8%), respectively), one patient in the vedolizumab treatment group had a serious CMV infection. Other serious infections (excluding CMV colitis) occurred in 125 (74.0%) of patients receiving vedolizumab versus 111 (67.3%) receiving placebo. These are listed by infection type (Extended Data Table 7). The most common serious infections were CMV reactivation (23.7% versus 18.2%); pneumonia (7.7% versus 8.5%); sepsis (5.3% versus 7.3%); and bacteremia (4.7% versus 5.5%) (Table 3). Serious abdominal and GI infections occurred in eight patients receiving vedolizumab (4.7%) and three receiving placebo (1.8%). Clostridioides infections occurred in 14 (8.3%) patients in the vedolizumab treatment group and six (3.6%) patients in placebo treatment group; of these 2.4% of patients in each treatment group had Clostridioides colitis (C.difficile colitis or Clostridioides colitis). For safety end points, statistical analyses were not adequately powered for comparisons between treatment groups. There were five patients with an AE of human polyomavirus infection; none of these was diagnosed as progressive multifocal leukoencephalopathy (PML). One patient with AML relapse and subsequent additional therapy developed PML, with a fatal outcome ~6 months after the last dose of vedolizumab. An independent adjudication committee deemed the most probable cause of this event to be the immunosuppressive treatment for AML. Secondary malignancies occurred in seven patients (4.1%) in the vedolizumab group and 16 (9.7%) in the placebo group. Post-transplant lymphoproliferative disease occurred in three patients (1.8%) in the placebo group only (Table 3).

Overall, 48 patients died during the period from first dose of study treatment to 18 weeks after last dose: 21 (12.4%) in the vedolizumab group and 27 (16.4%) in the placebo group. Leading causes of death were multiple organ dysfunction syndrome (3.0% versus 1.8%); AML recurrence (0.6% versus 2.4%); respiratory failure (1.8% versus 1.2%); pneumonia (1.2% versus 1.2%); and sepsis (0.0% versus 1.8%). Intestinal aGVHD was listed as cause of death in 0.0% versus 1.2% patients, aGVHD in liver (0.6% versus 0.6%) and aGVHD (0.6% versus 0.0%). An additional 17 patients died during the period from 18 weeks post-treatment to 12 months after HSCT: eight in the vedolizumab group and nine in the placebo group (Extended Data Table 8).

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Franklin RM, Kenyon KR, Tutschka PJ, Saral R, Richard Green W, Santos GW. Ocular manifestations of graft-vs-host disease. Ophthalmology. 1983;90:413. https://doi.org/10.1016/S0161-6420(83)34604-2.

Article CAS PubMed Google Scholar

Pellegrini M, Bernabei F, Barbato F, Arpinati M, Giannaccare G, Versura P, et al. Incidence, risk factors and complications of ocular graft-versus-host disease following hematopoietic stem cell transplantation. Am J Ophthalmol. 2021;227:2534. https://doi.org/10.1016/J.AJO.2021.02.022.

Article PubMed Google Scholar

Bray LC, Carey PJ, Proctor SJ, Evans RGB, Hamilton PJ, Carey TPJ. Ocular complications of bone marrow transplantation. Britishlournal Ophthalmol. 1991;75:6114.

CAS Google Scholar

Anderson NG, Regillo C. Ocular manifestations of graft versus host disease. Curr Opin Ophthalmol. 2004;15:5037. https://doi.org/10.1097/01.ICU.0000143684.22362.46.

Article PubMed Google Scholar

Sinha S, Singh RB, Dohlman TH, Taketani Y, Yin J, Dana R. Prevalence and risk factors associated with corneal perforation in chronic ocular graft-versus-host-disease. Cornea. 2020. https://doi.org/10.1097/ICO.0000000000002526.

Sinha S, Singh RB, Dohlman TH, Wang M, Taketani Y, Yin J, et al. Prevalence of persistent corneal epithelial defects in chronic ocular graft-versus-host disease. Am J Ophthalmol. 2020;218:296303. https://doi.org/10.1016/j.ajo.2020.05.035.

Article PubMed Google Scholar

Singh RB, Yuksel E, Sinha S, Wang S, Taketani Y, Luznik Z, et al. Prevalence of neurotrophic keratopathy in patients with chronic ocular graft-versus-host disease. Ocul Surf. 2022;26:138. https://doi.org/10.1016/j.jtos.2022.07.001.

Article PubMed Google Scholar

Wang S, Singh RB, Yuksel E, Musayeva A, Sinha S, Taketani Y, et al. Ocular pain in ocular graft-versus-host disease patients with neurotrophic keratopathy. Ocul Surf. 2022;26:1427. https://doi.org/10.1016/J.JTOS.2022.07.005.

Article PubMed Google Scholar

Chen Y, Wang S, Alemi H, Dohlman T, Dana R. Immune regulation of the ocular surface. Exp Eye Res. 2022;218:109007 https://doi.org/10.1016/J.EXER.2022.109007.

Article CAS PubMed PubMed Central Google Scholar

Foulsham W, Coco G, Amouzegar A, Chauhan SK, Dana R. When clarity is crucial: regulating ocular surface immunity. Trends Immunol. 2018;39:288301.

Article CAS PubMed Google Scholar

Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296 https://doi.org/10.1182/BLOOD-2011-06-364265.

Article CAS PubMed PubMed Central Google Scholar

Flowers MED, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214 https://doi.org/10.1182/BLOOD-2010-08-302109.

Article CAS PubMed PubMed Central Google Scholar

Hill GR, Ferrara JLM. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95:27549. https://doi.org/10.1182/BLOOD.V95.9.2754.009K25_2754_2759.

Article CAS PubMed Google Scholar

Carapito R, Jung N, Kwemou M, Untrau M, Michel S, Pichot A, et al. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD. Blood. 2016;128:197986. https://doi.org/10.1182/BLOOD-2016-05-719070.

Article CAS PubMed PubMed Central Google Scholar

Martin PJ, Levine DM, Storer BE, Warren EH, Zheng X, Nelson SC, et al. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood. 2017;129:7918. https://doi.org/10.1182/BLOOD-2016-09-737700.

Article CAS PubMed PubMed Central Google Scholar

Klmbt V, Wohlfeil SA, Schwab L, Hlsdnker J, Ayata K, Apostolova P, et al. A novel function for P2Y2 in myeloid recipient-derived cells during graft-versus-host disease. J Immunol. 2015;195:5795804. https://doi.org/10.4049/JIMMUNOL.1501357.

Article PubMed Google Scholar

Reinhardt K, Foell D, Vogl T, Mezger M, Wittkowski H, Fend F, et al. Monocyte-induced development of Th17 cells and the release of S100 proteins are involved in the pathogenesis of graft-versus-host disease. J Immunol. 2014;193:335565. https://doi.org/10.4049/JIMMUNOL.1400983.

Article CAS PubMed Google Scholar

Arafat SN, Robert MC, Abud T, Spurr-Michaud S, Amparo F, Dohlman CH, et al. Elevated neutrophil elastase in tears of ocular graft-versus-host disease patients. Am J Ophthalmol. 2017;176:4652. https://doi.org/10.1016/J.AJO.2016.12.026.

Article CAS PubMed Google Scholar

Mittal SK, Mashaghi A, Amouzegar A, Li M, Foulsham W, Sahu SK, et al. Mesenchymal stromal cells inhibit neutrophil effector functions in a murine model of ocular inflammation. Invest Ophthalmol Vis Sci. 2018;59:11918. https://doi.org/10.1167/iovs.17-23067.

Article CAS PubMed PubMed Central Google Scholar

Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:15975. https://doi.org/10.1038/nri3399.

Article CAS PubMed Google Scholar

Hlsdnker J, Ottmller KJ, Neeff HP, Koyama M, Gao Z, Thomas OS, et al. Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset. Blood. 2018;131:1858 https://doi.org/10.1182/BLOOD-2017-10-812891.

Article PubMed PubMed Central Google Scholar

An S, Raju I, Surenkhuu B, Kwon JE, Gulati S, Karaman M, et al. Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies. Ocul Surf. 2019;17:589614. https://doi.org/10.1016/J.JTOS.2019.03.010.

Article PubMed PubMed Central Google Scholar

Byun YS, Yoo YS, Kang MJ, Whang WJ, Na KS, Mok JW, et al. Marked infiltration of neutrophils at the upper palpebral conjunctiva in patients with chronic graft-versus-host disease. Ocul Surf. 2019;17:295302. https://doi.org/10.1016/J.JTOS.2018.12.007.

Article PubMed Google Scholar

Shikari H, Antin JH, Dana R. Ocular graft-versus-host disease: a review. Surv Ophthalmol. 2013;58:23351. https://doi.org/10.1016/J.SURVOPHTHAL.2012.08.004.

Article PubMed Google Scholar

Duffner UA, Maeda Y, Cooke KR, Reddy P, Ordemann R, Liu C, et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J Immunol. 2004;172:73938. https://doi.org/10.4049/JIMMUNOL.172.12.7393.

Article CAS PubMed Google Scholar

Stenger EO, Turnquist HR, Mapara MY, Thomson AW. Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity. Blood. 2012;119:5088 https://doi.org/10.1182/BLOOD-2011-11-364091.

Article CAS PubMed PubMed Central Google Scholar

Li H, Demetris AJ, McNiff J, Matte-Martone C, Tan HS, Rothstein DM, et al. Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells, and B cells does not prevent graft-versus-host disease induction. J Immunol. 2012;188:380411. https://doi.org/10.4049/JIMMUNOL.1102795.

Article CAS PubMed Google Scholar

Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS. The role of B cells in the pathogenesis of graft-versus-host disease. Blood. 2009;114:491927. https://doi.org/10.1182/BLOOD-2008-10-161638.

Article PubMed Google Scholar

Zeiser R, Blazar BR. Acute graft-versus-host diseasebiologic process, prevention, and therapy. N Engl J Med. 2017;377:216779. https://doi.org/10.1056/NEJMRA1609337/SUPPL_FILE/NEJMRA1609337_DISCLOSURES.PDF.

Article CAS PubMed PubMed Central Google Scholar

Toubai T, Mathewson ND, Magenau J, Reddy P. Danger signals and graft-versus-host disease: current understanding and future perspectives. Front Immunol. 2016;7. https://doi.org/10.3389/FIMMU.2016.00539.

Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009;284:2403548. https://doi.org/10.1074/JBC.M109.014266.

Article CAS PubMed PubMed Central Google Scholar

Koyama M, Cheong M, Markey KA, Gartlan KH, Kuns RD, Locke KR, et al. Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. J Exp Med. 2015;212:130321. https://doi.org/10.1084/JEM.20150329.

Article CAS PubMed PubMed Central Google Scholar

Zilliox MJ, Gange WS, Kuffel G, Mores CR, Joyce C, de Bustros P, et al. Assessing the ocular surface microbiome in severe ocular surface diseases. Ocul Surf. 2020;18:70612. https://doi.org/10.1016/J.JTOS.2020.07.007.

Article PubMed PubMed Central Google Scholar

Riemens A, Stoyanova E, Rothova A, Kuiper J. Cytokines in tear fluid of patients with ocular graft-versus-host disease after allogeneic stem cell transplantation. Mol Vis. 2012;18:797.

CAS PubMed PubMed Central Google Scholar

Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550 https://doi.org/10.1016/S0140-6736(09)60237-3.

Article CAS PubMed PubMed Central Google Scholar

Korngold R, Marini JC, de Baca ME, Murphy GF, Giles-Komar J. Role of tumor necrosis factor- in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant. 2003;9:292303. https://doi.org/10.1016/S1083-8791(03)00087-9.

Article CAS PubMed Google Scholar

Portero I, Gomez V, Arandojo C, Kreutzman A, Royg M, Ramirez A, et al. CCR7 as a new biomarker in graft-versus-host disease: T cells expressing the homing receptor CCR7 mediate the pathogenesis of Gvhd. Blood. 2014;124:3930 https://doi.org/10.1182/BLOOD.V124.21.3930.3930.

Article Google Scholar

Hill GR, Koyama M. Cytokines and costimulation in acute graft-versus-host disease. Blood. 2020;136:418 https://doi.org/10.1182/BLOOD.2019000952.

Article PubMed PubMed Central Google Scholar

Briones J, Novelli S, Sierra J. T-cell costimulatory molecules in acute-graft-versus host disease: therapeutic implications. Bone Marrow Res. 2011;2011:17. https://doi.org/10.1155/2011/976793.

Article CAS Google Scholar

Matte-Martone C, Liu J, Jain D, McNiff J, Shlomchik WD. CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL. Blood. 2008;111:388492. https://doi.org/10.1182/BLOOD-2007-11-125294.

Article CAS PubMed PubMed Central Google Scholar

Gallo PM, Gallucci S. The Dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front Immunol. 2013;4. https://doi.org/10.3389/FIMMU.2013.00138.

Land WG. Emerging role of innate immunity in organ transplantation part II: potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells. Transpl Rev (Orlando). 2012;26:7387. https://doi.org/10.1016/J.TRRE.2011.02.003.

Article Google Scholar

Teshima T. Th1 and Th17 join forces for acute GVHD. Blood. 2011;118:47657. https://doi.org/10.1182/BLOOD-2011-09-377325.

Article PubMed Google Scholar

Herretes S, Ross DB, Duffort S, Barreras H, Yaohong T, Saeed AM, et al. Recruitment of donor T cells to the eyes during ocular GVHD in recipients of MHC-matched allogeneic hematopoietic stem cell transplants. Invest Ophthalmol Vis Sci. 2015;56:2348 https://doi.org/10.1167/IOVS.14-15630.

Article CAS PubMed PubMed Central Google Scholar

Jardine L, Cytlak U, Gunawan M, Reynolds G, Green K, Wang XN, et al. Donor monocytederived macrophages promote human acute graft-versus-host disease. J Clin Invest. 2020;130:457486. https://doi.org/10.1172/JCI133909.

Article CAS PubMed PubMed Central Google Scholar

Baker MB, Altman NH, Podack ER, Levy RB. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med. 1996;183:264556. https://doi.org/10.1084/JEM.183.6.2645.

Article CAS PubMed Google Scholar

Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Hung ST, et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood. 2008;111:247684. https://doi.org/10.1182/BLOOD-2007-08-109678.

Article CAS PubMed PubMed Central Google Scholar

Maeda Y, Levy RB, Reddy P, Liu C, Clouthier SG, Teshima T, et al. Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease. Blood. 2005;105:20237. https://doi.org/10.1182/BLOOD-2004-08-3036.

Article CAS PubMed Google Scholar

Schmaltz C, Alpdogan O, Horndasch KJ, Muriglan SJ, Kappel BJ, Teshima T, et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood. 2001;97:288695. https://doi.org/10.1182/BLOOD.V97.9.2886.

Article CAS PubMed Google Scholar

Hartmann G, Weiner GJ, Krieg AM. CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci USA. 1999;96:930510. https://doi.org/10.1073/PNAS.96.16.9305.

Article CAS PubMed PubMed Central Google Scholar

Wang H, Yang Y-G. The complex and central role of interferon- in graft-versus-host disease and graft-versus-tumor activity. Immunol Rev. 2014;258:3044. https://doi.org/10.1111/imr.12151.

Article CAS PubMed PubMed Central Google Scholar

Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130:90 https://doi.org/10.1001/ARCHOPHTHALMOL.2011.364.

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Leukemia is an overarching term encompassing several subtypes of blood cancers. Blood cells are produced in the bone marrow, the spongy material inside bones. The bone marrow contains immature stem cells that develop and mature to become red blood cells, platelets, or different types of white blood cells.

When mutations occur in bone marrow stem cells, it can interfere with the bodys normal production of blood cells. This can start as a disease or disorder classified as a pre-leukemia state (and may or may not progress to leukemia), or it can start as leukemia.

Fadi Haddad, M.D., assistant professor of Leukemia, walked us through a few updates in leukemia research being presented at the 2024 American Society of Clinical Oncology Annual Meeting (ASCO).

Myelodysplastic syndrome (MDS) is a pre-leukemia state. Haddad explains, Myelo means related to the bone marrow, and dysplasia means abnormal growth. So, in patients with MDS, the bone marrow is abnormal. If left untreated, it could progress to acute myeloid leukemia (AML).

Azacitidine is approved as a treatment for MDS. Its given either as an intravenous (IV) infusion, or it's given as subcutaneous injections, meaning under the skin, says Haddad. Both options could be inconvenient for some patients. The IV infusion requires patients to come to the hospital repeatedly as long as they are receiving the treatment. The subcutaneous injections can be done at home, but they can cause hematomas and pain in the skin at the site of the injection. Compounding the inconvenience, patients may receive the treatment for several months or years.

In a study (Abstract 6509) presented by Guillermo Garcia-Manero, M.D., professor of Leukemia, researchers looked at the safety and efficacy of taking azacitidine orally, rather than via infusion or injection, for patients with low- or intermediate-risk MDS. While azacitidine taken orally is approved for maintenance therapy in patients with AML in remission, it is not currently approved for the treatment of MDS.

The study found that oral delivery of azacitidine had side effects similar to what weve seen with oral azacitidine in previous studies. The preliminary efficacy of the drug was also good. Close to 30% of patients saw hematologic improvement, which supports the continued evaluation of oral azacitidine in low- or intermediate-risk myelodysplastic syndrome, Haddad notes.

One area of interest in AML research is refining treatment both for older patients who need lower intensity treatment and for patients with AML that has come back (relapsed) or is not responding to treatment (refractory). The current standard of care is a combination of the drug venetoclax with either azacitidine or decitabine.

We've been investigating several compounds that are added to one of these combinations, Haddad notes. A study (Abstract 6511) presented by Maro Ohanian, D.O., associate professor of Leukemia, looks at the preliminary results of a clinical trial combining standard venetoclax and decitabine treatment with a new drug called BP1001. Adding BP1001 is supposed to enhance the cancer cell sensitivity to chemotherapy, so the effect of the chemotherapy will be stronger, says Haddad.

The study looked at this three-drug combination in older patients with newly diagnosed AML as well as in patients of all ages with relapsed or refractory AML. This triplet combination was safely administered to patients in both groups without new or unexpected toxicities, Haddad summarizes. The study is continuing enrollment and will expand to enroll more patients to collect data on efficacy.

Another treatment option for some subtypes of AML is a drug called gemtuzumab ozogamicin (GO). GO is a type of molecule known as an antibody drug conjugate. This means that two parts make up GO: an antibody that attaches to a biomarker on cancer cells and a chemotherapy drug. When we give patients this kind of treatment, the antibody attaches to the leukemia cell, and the drug enters the leukemia cell and leads to its death, Haddad explains.

The Food and Drug Administration (FDA) approved GO in 2017, but there have been concerns about side effects for patients who take GO and later receive bone marrow transplants. One of the side effects that we should pay attention to is hepatotoxicity negative impacts to the liver. In rare cases, it can cause hepatic veno-occlusive disease, or VOD. This is a very serious condition that can lead to liver failure if left untreated, says Haddad. Patients who take GO may be at a higher risk of developing VOD when they go on to receive bone marrow transplants.

To investigate these safety concerns, Partow Kebriaei, M.D., professor of Stem Cell Transplantation, led a multi-center effort to collect and analyze data (Abstract 6516) from adult patients with AML who received GO and went on to undergo bone marrow transplantation. The rates of VOD and the rates of mortality are similar to patients who got a transplant but did not take GO, says Haddad. This means the drug did not add much toxicity compared to what we see without the drug, and GO appears to be safe for use.

Two other research talks come from William Wierda, M.D., Ph.D., professor of Leukemia, and Julie Braish, M.D., a fellow in Leukemia. Wierda led the CAPTIVATE Phase II clinical trial (Abstract 7009). This trial looked at the combination of venetoclax and ibrutinib in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. Braish, working with Lucia Masarova, M.D., assistant professor of Leukemia, examined factors affecting outcomes in patients with myelofibrosis, another pre-leukemia state (Abstract 6514). These factors include the variant allele frequency of the JAK2 gene mutation and the presence or absence of cytopenias (lower than normal blood cell counts).

In addition to these presentations, MD Anderson researchers are giving two other oral presentations and numerous posters on leukemia research at the 2024 American Society of Clinical Oncology Annual Meeting. Our presentations at ASCO represent the impact our research is having in pushing a really broad range of leukemia and pre-leukemia research and treatment forward, says Haddad.

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What's new in leukemia research? - MD Anderson Cancer Center

A potential therapy for Alzheimer's disease highlights the important role of the immune system and how stem cell transplants can help revitalize aging cells linked to the neurodegenerative disease in mice.

(CN) Scientists on Tuesday revealed how young bone marrow stem cell transplants could be the future of treating immune cells that assist with the progression of Alzheimers Disease.

The findings in Science Advances come from a team of Chinese researchers who successfully transplanted bone marrow from two-month-old mice to restore the immune systems of their older counterparts affected by genetic and pathological indicators of Alzheimers disease.

Alzheimers is a progressive and fatal neurological disease that commonly affects people over the age of 65. Prevailing Alzheimers research links the disease to the buildup of amyloid beta and tau proteins in the brain, though other recent studies have found that approximately half of the genes associated with Alzheimer's are directly involved with the immune system.

As the researchers explain in the study, aged immune systems undergo immunosenescence the gradual decline of immune cell production and functionality which partly derives from aging bone marrow hematopoietic stem cells and progenitor cells.

Progenitor cells develop or differentiate into a predetermined type of cell. Hematopoietic stem cells are the source of peripheral immune cells like monocytes, macrophages and dendritic cells all of which can assist in the progression of neurodegenerative and neuroinflammatory diseases when they reach the brain.

The process of immunosenescence thus drives systemic aging and contributes to an increased susceptibility to age-related diseases like Alzheimer's disease. Using this information, the team realized that replenishing bone marrow with young hematopoietic stem cells can rejuvenate older immune cells and intervene in Alzheimers symptoms.

And thats not all they found.

Our findings revealed that aging induced changes in the gene expression in both innate and adaptive immune cells, aligned with the dysfunction of both innate and adaptive immune responses observed in aging animals or elderly individuals, such as diminished phagocytosis function of monocytes, impaired antiviral immunity of [natural killer] cells, elevated production of autoantibodies by B cells and expansion of cytotoxic T cells, the authors wrote.

The team also found that the genetic markers associated with aging were enriched for Alzheimers-related pathways, indicating an active link between senescent or deteriorating peripheral immune cells and the development of Alzheimer's especially monocytes.

Monocytes are a type of white blood cell that can clear amyloid beta proteins in the brain and plasma through phagocytosis (kind of like a cellular version of Pac-Man). Aging, however, can impair this ability and accelerate the occurrence of Alzheimers.

The findings from this study suggest that the diminished monocytic A clearance capacity is a consequence of the downregulation of key receptors involved in A phagocytosis within aging monocytes, the authors wrote. Collectively, these pieces of evidence indicate that the senescence of peripheral immune cells plays a critical role in the pathogenesis of AD, and rejuvenating peripheral immune cells in aging individuals may represent a promising intervention strategy.

As for the therapeutic value of young bone marrow transplants, the authors say there are many.

Not only did the young bone marrow improve the physical and behavioral symptoms of Alzheimers in older mice, but it decreased amyloid beta levels, lowered cerebral amyloid beta plaque and improved the mices overall cognition.

The findings also suggest that transplants can reverse one-third of Alzheimers-related gene expression, alleviate aged pathways, restore altered cell-to-cell communication in aging peripheral blood mononuclear cells, rescue dysfunctional monocytic functions and reduce levels of secreted triggers from aging cells called blood senescence-associated secretory phenotype or SASP factors.

The authors added that since young bone marrow transplants enhance the overall phagocytosis of monocytes, the same intervention is worth exploring for mice targeted by tau proteins, the other hallmark of Alzheimers. Future studies, they wrote, could focus on exploring other new strategies that can rejuvenate immune cells to advance the possibility of clinical translation.

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Excerpt from:
Stem cell transplants deliver promising treatments for mice with Alzheimer's disease - Courthouse News Service