From June 13 to 16, 2024, the 29th Annual Congress of the European Hematology Association (EHA) was held in Madrid, Spain. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from around the world every year to share and discuss innovative ideas and the latest scientific and clinical research results in hematology. At this year's EHA meeting, a study (S119) by Professor Xian Zhang from Beijing Lu Daopei Hospital was selected for oral presentation. The study explored immune reconstitution in R/R T-ALL/LBL patients following CD7 CAR-T therapy. “Oncology Frontier - Hematology Frontier” interviewed Professor Xian Zhang to introduce and interpret the study's content and topics related to the treatment of R/R T-ALL/LBL.

Study Overview

Exploring Immune Reconstitution After CD7 CAR-T Therapy in Patients with Relapsed/Refractory Acute T-cell Lymphoblastic Leukemia/T-cell Lymphoblastic Lymphoma (R/R T-ALL/LBL)

Background

CD19 CAR-T therapy has shown outstanding efficacy in treating relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL), with complete remission rates (CR) reaching about 90%. Recent studies indicate that CD7 CAR-T therapy also exhibits excellent therapeutic effects in relapsed or refractory acute T-cell lymphoblastic leukemia/T-cell lymphoblastic lymphoma (R/R T-ALL/LBL). While the side effects of CD19 CAR-T have been proven not to significantly affect the immune function of patients, the cytotoxic effects of CD7 CAR-T, especially concerning T-cell toxicity, remain uncertain.

Objective

To investigate immune reconstitution in patients with R/R T-ALL/LBL following CD7 CAR-T therapy.

Methods

This study enrolled 60 patients with R/R T-ALL/LBL who received CD7 CAR-T (NS7CAR-T) therapy between December 2020 and June 2022. Simultaneously, another 60 patients with R/R B-ALL received CD19 CAR-T therapy for comparison. The data were extracted from two independent clinical trials. Patients underwent lymphocyte depletion therapy before CAR-T infusion and typically received consolidation therapy with allogeneic hematopoietic stem cell transplantation (allo-HSCT) post-infusion. We analyzed the incidence of infections (diagnosed etiologically and through imaging) from the infusion of CAR-T cells to allo-HSCT.

Flow cytometry was used to detect the absolute count of total CD3+ T cells at days 0, 4, 8, 11, 14, 21, and 28 after CD7 CAR-T cell infusion in 40 patients. The proportions and absolute counts of CD7+ CD3+ T cells, CD7- CD3+ T cells, and CAR-T cells/CD7- CD3+ T cells were then measured.

Results

Regarding efficacy, 94.4% (51/54) of R/R T-ALL/LBL patients achieved complete remission (CR) of the bone marrow after CD7 CAR-T therapy.

In terms of safety:

1. 53/60 (88.3%) patients experienced mild cytokine release syndrome (CRS, ≤ Grade II), with six cases of Grade III CRS and one case of Grade IV CRS. Regarding neurotoxicity, there were only two Grade I cases and one Grade IV case.
2. The overall infection incidence showed no statistical difference between the CD19 CAR-T and CD7 CAR-T groups, with rates of 28.3% vs. 36.7% (p=0.33). However, fungal infection rates were notably higher in the CD7 CAR-T group compared to the CD19 CAR-T group, at 10% vs. 1.7% (P=0.05).

Additionally, we analyzed the proportions and absolute counts of CD7+/CD7- T cells in CD3+ T cells, and the proportions and absolute counts of CAR-T and non-CAR-T cells in CD7- CD3+ T cells among 40 patients treated with CD7 CAR-T. The results showed that before CAR-T infusion, peripheral blood had a low level of CD7- cells (averaging about 7.5%). After CAR-T infusion, the number of CD7+ T cells significantly decreased over time, while CD7- T cells gradually increased. Among the CD7- T cells, non-CAR-T CD7- T cells exhibited a significant increase and maintained a high level.

Conclusion

This study demonstrates that R/R T-ALL/LBL patients did not experience severe side effects after receiving CD7 CAR-T therapy, with no significant increase in overall infection rates. However, the fungal infection rate was relatively higher in the CD7 CAR-T group compared to the CD19 CAR-T group. Moreover, we found that CD7+ T cells significantly decreased after CD7 CAR-T infusion, while non-CAR-T CD7- T cells increased markedly, potentially maintaining immune function. Thus, CD7 CAR-T does not substantially impact immune function. However, the long-term effects on immune reconstitution after allo-HSCT and CD7 CAR-T require further observation beyond the two-month follow-up period.

Expert Interview

Oncology Frontier – Hematology Frontier: Congratulations on your research being selected for oral presentation at the EHA conference. Could you briefly introduce the background and main objectives of your team’s study?

Professor Xian Zhang: Firstly, this is a very meaningful clinical study focused on patients with relapsed/refractory acute T-cell lymphoblastic leukemia/lymphoma (R/R T-ALL/LBL). Prior to the advent of CD7 CAR-T, treating these patients was extremely challenging, with limited treatment options and high mortality rates. Since September 2020, our team began exploring the use of CD7 CAR-T in R/R T-ALL/LBL, enrolling over 200 patients to date. The results show significant efficacy, with complete remission rates exceeding 90%. However, a key issue is understanding the immune reconstitution and infection status of R/R T-ALL/LBL patients following CD7 CAR-T therapy. There is currently no clear data on this topic domestically or internationally, so this study aims to provide detailed clinical data to clarify this issue and offer some reliable conclusions to guide clinicians.

Oncology Frontier – Hematology Frontier: Your study investigated the impact of CD7 CAR-T therapy on immune reconstitution in R/R T-ALL/LBL patients. Could you elaborate on the main findings? What is their significance for further research or clinical application of CD7 CAR-T therapy?

Professor Xian Zhang: Over the past decade, CD19 CAR-T has achieved remarkable therapeutic results in treating relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL), with complete remission rates exceeding 90%. Moreover, studies have confirmed that CD19 CAR-T does not significantly impact the immune function of patients. However, CD7 CAR-T targets T cells, which are crucial immune cells. The concern is whether depleting T cells will severely affect the patient’s immune function. Although our clinical observations over the past three years have not shown significant immune function disruption, this study aimed to elucidate the immune reconstitution status following CD7 CAR-T therapy in R/R T-ALL/LBL patients. We included 60 patients treated with CD7 CAR-T and compared them with 60 patients treated with CD19 CAR-T. The results indicated no significant difference in overall infection incidence between the two groups, although fungal infection rates were higher in the CD7 CAR-T group. However, this may be due to sample size limitations. Overall, the infection rates following CD7 CAR-T and CD19 CAR-T therapy were similar.

To delve deeper into the reasons, this study conducted detailed subgroup analyses of T-cell function after CD7 CAR-T therapy, focusing on the proportions and absolute counts of CD7+/CD7- T cells in CD3+ T cells, and the proportions and absolute counts of CAR-T and non-CAR-T cells in CD7- CD3+ T cells. We were surprised to find that after CD7 CAR-T infusion, the number of CD7+ cells significantly decreased while CD7- cells gradually increased over time. Notably, within the CD7- cells, as CAR-T cell levels decreased over time, non-CAR-T CD7- T cells continued to rise and maintained a relatively high level. Literature suggests that CD7- T cells can also provide normal immune functions. Therefore, we concluded that CD7 CAR-T therapy for R/R T-ALL/LBL does not lead to significant immune function issues, as CD7- T cells replace CD7+ T cells in providing and maintaining essential immune functions.

Oncology Frontier – Hematology Frontier: Given the impressive efficacy of CD7 CAR-T therapy in R/R T-ALL/LBL, what are your team’s plans and prospects for further research on its long-term impacts?

Professor Xian Zhang: Currently, CD7 CAR-T shows excellent efficacy in treating R/R T-ALL/LBL, with complete remission rates reaching 90%, and effectively clearing extramedullary lesions. During the study’s observation period, patients’ immune functions were not significantly affected post-treatment. Regarding the slightly higher fungal infection rate, we believe that expanding the patient sample size and extending the follow-up period are necessary to clarify this issue further. Additionally, the median duration of response (mDOR) for CD7 CAR-T is around three months, and our center typically bridges allo-HSCT within 2-3 months after CAR-T infusion. We have a significant research interest in the immune function status of patients post-allo-HSCT. Our next step will be to conduct in-depth research in this area to provide more data and information.

Oncology Frontier – Hematology Frontier: Finally, in terms of R/R T-ALL/LBL treatment, what other promising treatment methods or research directions do you believe are worth further exploration?

Professor Xian Zhang: Firstly, we discussed the encouraging progress of CD7 CAR-T in R/R T-ALL/LBL treatment, achieving a CR of over 90%. However, some patients do not respond to this therapy, making the exploration of new targets a future research direction, such as the CD5 target. Secondly, since R/R T-ALL/LBL patients require bridging allo-HSCT after CD7 CAR-T therapy, some patients cannot undergo allo-HSCT (due to intolerance or post-transplant status). How to maintain their disease-free survival (DFS) is a problem we need to explore further, such as using new small-molecule drugs and consolidating with CD5 CAR-T. These are currently in the conceptual stage of clinical research and have not yet been applied clinically. Additionally, expanding the application of CD7 CAR-T to other malignant tumor diseases is also a direction worth exploring. There is already some research data, such as its application in peripheral T-cell lymphoma (PTCL) and CD7-positive acute myeloid leukemia. Finally, new targeted drugs, antibody-drug conjugates (ADCs), and bispecific antibodies are also promising treatments for R/R T-ALL/LBL.