Editor's Note: With the continuous advancement of immunotherapy technologies, CD7 CAR-T cell therapy is emerging as a new option for treating leukemia and lymphoma, showing significant potential. Recent clinical studies have revealed multiple new developments in CD7 CAR-T cell therapy. However, challenges remain, such as improving safety, reducing side effects, and optimizing treatment protocols to enhance long-term efficacy. At the recent "2024 Nanjing Lymphoma Forum," Professor Yongxian Hu from The First Affiliated Hospital of Zhejiang University School of Medicine delivered an excellent report titled "New Advances in CD7 CAR-T Cell Therapy." Following the forum, Hematology Frontier invited Professor Hu for an interview to further discuss this topic.Hematology Frontier: CAR-T therapy is increasingly being used earlier in treatment lines. Studies like ZUMA-7 and ZUMA-12 have demonstrated the efficacy of frontline CAR-T therapy. What factors can further enhance the efficacy of early-line CAR-T therapy?
Professor Yongxian Hu: The effectiveness of early-line CAR-T therapy is influenced by several factors, the first being the number of treatment lines. As the number of chemotherapy cycles increases, the quantity and proliferative capacity of the patient’s T cells gradually decrease, particularly those essential for CAR-T cell preparation, such as initial T cells and central memory T cells (Tcm). Their proportion declines with more lines of chemotherapy, impacting the success rate of CAR-T cell preparation and the expansion and efficacy of CAR-T cells after infusion. Therefore, we recommend collecting T cells for CAR-T cell preparation as early as possible, preferably when the patient has undergone fewer lines of chemotherapy, to improve the success rate and achieve better efficacy. If we compare CAR-T cells to seeds, the patient’s condition is the soil. Seeds need fertile soil to grow. The patient’s condition includes physical fitness, immune function, and the tumor microenvironment. Only when these conditions are ideal can CAR-T cells expand more effectively, improving efficacy and increasing the possibility of a cure. Clinical studies also suggest that the earlier CAR-T cell therapy is used in the treatment line, the better the treatment outcomes. For example, the ZUMA-1 study targeted patients with third-line or higher treatment, while ZUMA-7 targeted second-line treatment, and ZUMA-12 focused on high-risk patients in the first-line setting.
Secondly, the timing of the infusion affects the efficacy of early-line CAR-T therapy. Studies show that the efficacy of CAR-T cells is closely related to the infusion timing. Infusing within 36 days of leukapheresis significantly improves overall survival (OS) and progression-free survival (PFS) compared to later infusions. In many cases, delayed infusion is due to bridging therapy, which can effectively reduce tumor burden. However, not all patients require bridging therapy. According to current clinical guidelines, bridging therapy is generally not recommended for patients with stable conditions post-leukapheresis. Unnecessary bridging therapy and evaluations may delay CAR-T cell infusion, impacting its efficacy. The efficacy of CAR-T cell therapy depends mainly on the CAR-T cells themselves rather than bridging therapy or the state after bridging therapy. Therefore, we recommend early infusion once CAR-T cells are ready.
In our clinical research, we also found that the earlier CAR-T cell therapy is used, the better the outcomes for patients. This is partly due to the patient’s physical fitness and organ function. We recommend collecting T cells for CAR-T preparation and using CAR-T cells as early as possible when feasible. Additionally, as the number of chemotherapy lines increases, tumor cells may undergo various mutations, which can affect the efficacy of CAR-T cell therapy.
Hematology Frontier: CD7-positive malignancies, such as highly aggressive lymphomas or leukemias, have rapid disease progression, poor prognosis, and high recurrence rates. What are the recent clinical research advancements in CD7 CAR-T cell therapy, and what challenges remain in its clinical application?
Professor Yongxian Hu: There have been significant clinical advancements in CD7 CAR-T cell therapy. Currently, CAR-T cells can be sourced in three ways: universal CAR-T cells, autologous CAR-T cells, and donor-derived CAR-T cells. Universal CAR-T cells are prepared using T cells from healthy donors, which are then cryopreserved for future use. Autologous CAR-T cells are derived from the patient’s own peripheral blood T cells. However, a potential issue with autologous CAR-T cells is contamination by tumor T cells. Therefore, strict purification is necessary during ex vivo preparation. Universal CAR-T cells, due to their ample supply and convenience, can be rapidly provided according to clinical needs and have relatively lower preparation costs, making them more accessible in the future.
Hematology Frontier: As a co-corresponding author, could you elaborate on the major innovations of the “integrated CD7 CAR-T cell therapy and haploidentical allogeneic HSCT” approach described in your recent study published in NEJM? What research outcomes have been achieved so far?
Professor Yongxian Hu: Our study’s major innovations include, first, achieving thorough eradication of leukemia or lymphoma cells in patients. It is generally believed that the fewer leukemia cells present in the patient before hematopoietic stem cell transplantation, the lower the post-transplant recurrence risk. Therefore, we use CAR-T cell therapy to thoroughly eliminate leukemia cells before transplantation, clearly correlating with reduced recurrence rates. Second, our strategy avoids the need for myeloablative conditioning chemotherapy and graft-versus-host disease (GVHD) prophylactic drugs. Because our CD7 CAR-T cells can completely clear the bone marrow, we can promptly perform hematopoietic stem cell infusion when the patient enters bone marrow suppression. This approach significantly reduces the toxicity and side effects of these drugs, enhancing treatment safety. Third, CD7 CAR-T cells can persist in the patient’s body, providing long-term anti-leukemia effects. These persistent CAR-T cells continuously recognize and eliminate residual leukemia cells, further reducing recurrence risks. Fourth, following CAR-T cell therapy and hematopoietic stem cell transplantation, the patient experiences immune reconstitution with CD7-negative T cells, which can exert graft-versus-leukemia effects, thereby reducing recurrence rates.
Hematology Frontier: What insights can clinical researchers gain from the design, implementation, and publication of this study? What are your team’s future research plans?
Professor Yongxian Hu: Most of our clinical research is derived from clinical practice. We noticed that even after CAR-T cell therapy followed by allogeneic hematopoietic stem cell transplantation, patients still faced a risk of recurrence. We hypothesized that if CAR-T cells could persist post-transplant without being eliminated, they might reduce post-transplant recurrence risks. To test this hypothesis, we explored a treatment strategy that does not require conditioning chemotherapy. Additionally, we observed some intriguing clinical phenomena during our research. Collaborating with basic research teams, we conducted studies to delve into the mechanisms behind these phenomena. Our research has yielded positive results, and we aim to apply these findings in clinical practice to provide more precise guidance for clinical treatment, ultimately improving treatment outcomes and patient prognosis.
In the future, we plan to expand the sample size and initiate a nationwide multicenter clinical study to validate the safety and efficacy of this treatment approach. We will also conduct long-term follow-up on patients to observe long-term outcomes and potential complications, providing comprehensive data support for clinical treatment.
