In a recent study published in The New England Journal of Medicine, researchers developed an innovative all-in-one treatment protocol that combines CD7 chimeric antigen receptor T-cell therapy with subsequent haploidentical hematopoietic stem cell transplantation. This approach significantly advances the treatment of CD7+ hematological malignancies by eliminating the need for myeloablative chemotherapy and immunosuppressants for graft-versus-host disease prophylaxis.

Chimeric antigen receptor (CAR) T-cell therapy utilizes synthetic antigen receptors targeting T lymphocytes to attack tumor cells specifically. To date, CAR T-cell therapies have shown unprecedented efficacy in B-cell malignancies. In contrast, there are significantly fewer clinical trials of CAR T-cell therapy against T-cell malignancies.1 Outcomes of T-cell lymphomas and relapsed T-cell acute lymphoblastic leukemia (T-ALL) patients are notably poor compared to those of their B-cell counterparts, with an estimated 5-year overall survival rate of only 32% for T-cell lymphomas patients and 7% for relapsed T-ALL patients.2 The challenge in treating T-cell malignancies lies in the lack of ideal target antigens. Several studies, including a recent study published in Cell Research,3 identified CD7 as a promising target for CAR-T therapy in the treatment of T-cell malignancies. However, in these clinical trials of CD7 CAR T-cells, researchers frequently observed that CD7 CAR T-cell treatment resulted in incomplete hematologic recovery and pancytopenia, presenting a significant clinical challenge.4

Recently, The New England Journal of Medicine reported on a novel all-in-one treatment regimen developed by a team from Hangzhou, China (hereafter referred to as the Hangzhou Protocol).5 In this clinical trial of CD7 CAR T-cell therapy for CD7+ hematological malignancies, including T-cell malignancies and acute myeloid leukemia (AML), Hu et al. observed that CD7 CAR T-cell treatment induced severe bone marrow hypocellularity, pancytopenia, and immunosuppression, aligning with previous reports. The first patient experienced persistent grade 4 pancytopenia for three months following CAR T-cell infusion and consequently developed severe infections. A salvage haploidentical hematopoietic stem cell transplantation (HSCT) was thus performed, without additional pharmacologic pre-HSCT conditioning regimens. Favorable engraftment of hematopoietic stem cells (HSCs) and immune reconstitution were observed, suggesting that the potent immunosuppressive functions of CD7 CAR T-cells, coupled with prior lymphodepletion, might replace the need for traditional chemotherapy conditioning. The subsequent 9 patients of similar conditions were promptly subjected to HSCT within one month after receiving CD7 CAR T-cell therapy without chemotherapy conditioning and immunosuppressive drugs for graft-versus-host disease (GVHD) prophylaxis. All 10 patients treated with the Hangzhou Protocol achieved complete remission. Pancytopenia was successfully relieved after allogeneic HSCT. Eight patients had full donor chimerism and immune reconstitution with a mild and manageable incidence of acute GVHD. Six of these patients remained in minimal residual disease-negative complete remission. The one-year overall survival rate increased to 68%. Collectively, this all-in-one Hangzhou Protocol offers a promising therapeutic option to CD7+ tumor patients.

Traditional CAR T-cell therapy followed by bridging HSCT involves longer intervals, chemotherapy conditioning, and the use of immunosuppressants for GVHD prophylaxis. Notably, the Hangzhou Protocol offers quadruple clinical benefits (Fig.1). First, CD7 CAR T-cell therapy efficiently eliminates CD7+ cancer cells in patients. More than 95% of patients with T-cell malignancies have CD7+ tumor cells,6 and about 30% of AML patients exhibit CD7 expression.7 In the trial, all treated patients including those with both T-cell malignancies and AML achieved complete remission. Second, the Protocol eliminates the need for pharmacologic myeloablation before HSCT, thereby avoiding its associated toxic effects. This is particularly beneficial for patients who have severe physiological issues or are in poor condition and who often are ineligible for allogeneic HSCT. Third, the Hangzhou Protocol does not require the use of immunosuppressants for GVHD prophylaxis, thus avoiding subsequent immunodeficiency issues. This allows the patients immune system to recover more rapidly. However, the mechanism behind this benefit requires further investigation. It is reported that CD7 plays a costimulatory role in T-cell signaling.8 Therefore, CD7 T cells, which are generated post CD7 CAR T-cell treatment, display reduced functionality and consequently a lower degree of GVHD. Lastly, the all-in-one treatment regimen maintains the persistence of CAR T-cells and supports their long-term immune surveillance function along with the graft-versus-leukemia effect. This maximizes the benefits of long-term immune surveillance by CAR T-cells and minimizes the risk of tumor relapse.

The figure illustrates clinical benefits of the Hangzhou Protocol in the context of CD7 CAR T-cell therapy for hematological malignancies. The top left section highlights the targeted tumor clearance capability of CD7 CAR T-cells, which are effective against both T-cell malignancies and AML. The top right section demonstrates the elimination of the need for myeloablative chemotherapy, reducing patient exposure to toxic effects. The bottom left section shows the avoidance of immunosuppressants in GVHD prophylaxis, which not only facilitates quicker immune system recovery but also minimizes complications from immunosuppression and associated drug side effects. Finally, the bottom right section details the sustained CAR T and GVL effects, which are crucial for preventing tumor relapse and supporting long-term immune surveillance. GVL graft-versus-leukemia, BM bone marrow, GVHD graft-versus-host disease, AML acute myeloid leukemia, CAR chimeric antigen receptor.

Several questions remain to be addressed regarding CD7 CAR T-cell therapy. One interesting question is why CD7 CAR T-cells suppress the patients hematopoiesis, causing severe pancytopenia, bone marrow aplasia, and immunosuppression. CAR T-cell-induced cytokine release syndrome could induce cytokine-associated pancytopenia.9 Conversely, it is also possible that minimal expression of CD7 on HSCs might induce CAR T-cell cytotoxicity. Furthermore, the mechanisms behind the successful engraftment and immune reconstitution of donor-derived stem cells in the presence of CD7 CAR T-cells while the patients own hematopoiesis is suppressed, are intriguing and warrant further investigation. Another interesting point is why CD7 CAR T-cell persistence is significantly longer than that of CD19 CAR T-cells. CAR tonic signaling has been reported to play a crucial role in regulating in vivo persistence and fitness of CAR T-cells.10,11 Thus, it is necessary to explore whether CD7 knockout in CD7 CAR T-cells affects CAR tonic signaling. All these questions need to be addressed in future studies to enhance our understanding and improve the efficacy of CD7 CAR T-cell therapy.

More here:
All-in-one Hangzhou Protocol: killing four birds with one stone | Cell Research - Nature.com

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