CAR-T cell therapy has achieved transformative success in lymphoid malignancies, yet its application in acute myeloid leukemia (AML) remains highly challenging. Against this backdrop, a sequential strategy integrating CD7-targeted CAR-T cell therapy with haploidentical hematopoietic stem cell transplantation (HSCT) has demonstrated encouraging potential.
To elucidate the key challenges of CAR-T therapy in AML, the rationale for selecting CD7 as a therapeutic target, and the core findings of this innovative strategy, Hematology Frontier invited Prof. Yongxian Hu of The First Affiliated Hospital, Zhejiang University School of Medicine for an in-depth discussion on its clinical value and future directions, with the aim of providing new insights into therapeutic breakthroughs in AML.
Hematology Frontier: CAR-T therapy has achieved remarkable success in lymphoid malignancies but continues to face major obstacles in AML. Compared with lymphoid cancers, what are the unique challenges of CAR-T therapy in AML, and what was the rationale for selecting CD7 as the target in your study?
Prof. Yongxian Hu:
CAR-T therapy has shown substantial clinical efficacy in both B-cell and T-cell malignancies. In B-cell tumors, CAR-T therapies targeting CD19 and CD22 have achieved durable responses, while in T-cell malignancies, targets such as CD7 and CD5 have also demonstrated clinical benefit.
However, in AML, an ideal CAR-T target has yet to be identified. This is largely due to the biological characteristics of AML: most candidate antigens expressed on leukemic blasts are also widely expressed on normal hematopoietic stem and progenitor cells. Targeting such antigens would result in severe on-target, off-tumor toxicity—particularly profound and prolonged myelosuppression—leading to failure of hematopoietic recovery and life-threatening infections.
Although some antigens are expressed only in specific AML subpopulations, CAR-T cells targeting these markers often show insufficient in vivo expansion and limited persistence, resulting in inadequate antileukemic activity. Consequently, unlike in ALL or lymphoma, no broadly applicable CAR-T target has been established in AML to date.
Our team identified that CD7 is aberrantly expressed in approximately 20% of AML patients. Based on this finding, we developed CD7-targeted CAR-T cells to achieve precise elimination of CD7-positive AML. Early clinical studies confirmed that CD7-positive AML blasts can be efficiently recognized and eradicated by CD7 CAR-T cells.
Hematology Frontier: Your results showed a best overall response rate of 62.5% in patients with high CD7 expression. However, some patients did not respond. What do you believe are the main reasons for treatment failure in these cases?
Prof. Yongxian Hu:
Although the best overall response rate exceeded 60%, lack of response in some patients is primarily attributable to antigen heterogeneity in AML. Not all leukemic cells express CD7, and even in CD7-positive patients, expression is often restricted to only a subset of leukemic clones.
As a result, CD7-negative leukemic cells escape CAR-T–mediated killing, leading to residual disease and treatment failure. In non-responding cases, the remaining leukemic burden is predominantly composed of CD7-negative clones, which cannot be targeted by CD7 CAR-T cells.
Hematology Frontier: Your study supports CD7 as a viable target and highlights the importance of subsequent HSCT/HCB in maintaining remission. How do you think this strategy will influence the AML treatment landscape, and what are your expectations for the future development of CD7-targeted CAR-T therapy?
Prof. Yongxian Hu:
We recognize that relapse driven by CD7-negative clonal escape remains a key challenge. Building on our prior work published in The New England Journal of Medicine, we demonstrated that after CD7 CAR-T therapy, donor hematopoietic stem cells can be reinfused during the marrow aplasia phase, facilitating immune and hematopoietic reconstitution.
This integrated strategy offers dual antileukemic mechanisms:
- A graft-versus-leukemia (GVL) effect from donor cells
- Long-term persistence of CD7 CAR-T cells, enabling sustained targeted cytotoxicity
Together, these effects enhance leukemic clearance and reduce relapse risk.
Nevertheless, effective eradication of CD7-negative AML clones remains an unmet need. We are conducting mechanistic studies to clarify the biological basis of intra-patient CD7 expression heterogeneity. Our goal is to explore whether pharmacologic induction can convert CD7-negative leukemic cells into CD7-positive ones, rendering them susceptible to CAR-T therapy.
In parallel, we are actively searching for additional targets on CD7-negative leukemic cells, with the aim of developing dual-target CAR-T strategies or sequential cellular therapies to achieve comprehensive eradication of AML.
With continued advances, we believe that cellular immunotherapy will ultimately overcome AML.
Study Abstract
Abstract 1040
Sequential CD7 CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation Without GVHD Prophylaxis in Relapsed/Refractory CD7-Positive Hematologic Malignancies: An Interim Analysis of a Phase I Study
Background: CD7-targeted CAR-T cell therapy has emerged as a promising approach for inducing remission in relapsed/refractory (R/R) CD7-positive hematologic malignancies. Previously, we reported the safety and efficacy of a novel integrated strategy—sequential CD7 CAR-T therapy followed by haploidentical HSCT without myeloablative conditioning or GVHD prophylaxis—in 10 R/R patients (NEJM, 2024). This report presents an interim analysis of an ongoing prospective, single-arm phase I study evaluating this strategy in a larger cohort.
Methods: Patients with R/R CD7-positive hematologic malignancies, regardless of prior allo-HSCT history, were eligible. Lymphodepletion consisted of fludarabine, cyclophosphamide, and etoposide, followed by infusion of CD7 CAR-T cells (2×10⁶ cells/kg) derived from either prior donors or newly selected haploidentical donors. Upon achieving CRi, patients received haploidentical HSCT without conditioning or GVHD prophylaxis. Primary endpoints were safety and tolerability; secondary endpoints included chimerism, progression-free survival (PFS), and overall survival (OS).
Results: As of August 5, 2025, 19 patients were enrolled; 15 (78.9%) had ≥3 months of follow-up. Median age was 48 years. Diagnoses included AML (n=10), T-LBL (n=5), and T-ALL (n=4). Thirteen patients had received ≥3 prior therapies, and eight had prior allo-HSCT.
All CAR-T products were successfully manufactured. All patients achieved MRD-negative CRi after CAR-T infusion, with most proceeding to transplantation within one month. CRS occurred in 84.2% of patients. Post-transplant acute GVHD occurred in 58.6%, all manageable. Among 17 evaluable patients, 16 achieved full donor chimerism at one month. Only one case of chronic GVHD was observed.
At a median follow-up of 7.1 months, 13 patients were alive, and 11 were disease-free. CD7-negative relapse occurred in five patients. Twelve-month OS and PFS were 54.8% and 48.7%, respectively.
Conclusion: This interim analysis further supports the safety, feasibility, and efficacy of this integrated strategy in R/R CD7-positive malignancies, offering a promising option—particularly for patients unsuitable for conventional allo-HSCT.
Expert Profile
Prof. Yongxian Hu
The First Affiliated Hospital, Zhejiang University School of Medicine
Vice Dean, Zhejiang University School of Medicine Chief Physician, PhD Supervisor Qiushi Distinguished Professor Recipient of the 2024 National Science Fund for Distinguished Young Scholars
Deputy Director, Bone Marrow Transplantation Center Member, Lymphoid Diseases Group, Chinese Society of Hematology
Author of over 50 high-impact publications in NEJM, Nature, JAMA Oncology, Lancet Haematology, Cell Research, and Blood. Editor-in-Chief of 100 Questions on CAR-T Cell Immunotherapy (People’s Medical Publishing House).
