Treatment options remain extremely limited for patients with relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) who relapse after CD7 CAR-T therapy. Although previous studies of humanized CD5 CAR-T cells demonstrated encouraging antitumor activity, long-term follow-up revealed a significant safety challenge: a high incidence of severe and sometimes fatal infections.At the 2026 European Hematology Association (EHA) Congress, the team led by Dr. Jing Pan from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, and Beijing Gobroad Hospital presented groundbreaking data on a novel dual-epitope nanobody-based CD5 CAR-T (NbCD5 CAR-T) platform. Building upon their earlier work published in Nature Medicine, the study systematically evaluated the expansion kinetics, toxicity profile, and clinical efficacy of this next-generation CAR design.
In an interview with Oncology Frontier – Hematology Frontier, Dr. Pan discussed how this innovative CAR-T construct may provide a safer and more effective immunotherapeutic strategy for patients with relapsed or refractory T-ALL.
A Faster and More Potent CAR-T Design
Oncology Frontier – Hematology Frontier:
Your team previously developed humanized CD5 CAR-T therapy with promising efficacy. In this study, a dual-epitope camelid nanobody-based CD5 CAR design achieved substantially faster in vivo expansion. Mechanistically, how does this new structure enhance CAR-T function, and what advantages does it offer compared with traditional scFv-based CARs?
Dr. Jing Pan:
Our team began developing CD5 CAR-T therapies in 2021. In our earlier studies, we used a humanized dual-epitope CD5 CAR-T product to treat patients with relapsed or refractory T-ALL, particularly those who had failed prior CD7 CAR-T therapy. Those results were published in Nature Medicine in 2024.
While the short-term efficacy was highly encouraging, long-term follow-up revealed significant safety concerns, particularly regarding viral reactivation and fatal infections.
To address these challenges, we initiated a comprehensive effort to optimize the CAR structure. Our goal was to identify a construct with faster expansion, stronger target affinity, and more potent antitumor activity.
After evaluating multiple antibody platforms, including both humanized antibodies and nanobodies, we identified a unique dual-epitope nanobody-based CD5 CAR design. Preclinical studies demonstrated significantly superior expansion capacity and tumor-killing activity compared with the earlier humanized dual-epitope CD5 CAR-T platform.
Based on these findings, we advanced the construct into clinical testing.
The initial clinical results have been highly encouraging. Among the first ten treated patients, the novel NbCD5 CAR-T demonstrated both excellent efficacy and a favorable safety profile. Cytokine release syndrome (CRS) duration was significantly shortened, and CAR-T expansion occurred substantially earlier than previously observed.
As the saying goes, “speed is the ultimate weapon.” When CAR-T cells eliminate tumor cells more rapidly and efficiently, treatment-related toxicities naturally become less severe. Long-term follow-up has further shown that no deaths from severe infections have occurred in this cohort, which was one of the key motivations for presenting these data.
Why Faster Expansion Matters
Oncology Frontier – Hematology Frontier:
The median expansion peak occurred on day 10, substantially earlier than in previous hCD5 CAR-T studies. What clinical benefits does this improved expansion kinetics provide? Does it directly reduce infections or early disease progression?
Dr. Jing Pan:
An earlier expansion peak indicates that CAR-T cells have rapidly completed their tumor-killing mission.
CAR-T expansion typically reaches its maximum only after CD5-positive target cells have been effectively eliminated. Therefore, accelerated expansion reflects more efficient tumor clearance.
From a clinical perspective, faster expansion significantly shortens the duration of active tumor killing. This translates into lower risks and shorter durations of serious toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and macrophage activation syndrome (MAS).
When these complications are minimized, tissue damage is reduced accordingly, which may ultimately lower the long-term risk of severe infections.
Our strategy is therefore straightforward: enhance CAR-T expansion efficiency, accelerate tumor eradication, and thereby reduce the incidence of serious viral infections over the long term.
The Challenge of Antigen Escape
Oncology Frontier – Hematology Frontier:
Although the study achieved a high remission rate, relapses associated with CD5 downregulation or loss were still observed. How do you view the challenge of antigen escape? Do you believe the future lies in multi-target CAR-T approaches or in optimizing integration with transplantation?
Dr. Jing Pan:
Antigen escape remains a universal challenge for all CAR-T therapies.
While dual-target and multi-target approaches are commonly considered solutions, T-cell CAR-T therapies face an additional and unique challenge: T-cell immune deficiency.
If this issue is not adequately addressed, even sophisticated multi-target CAR-T platforms may ultimately function only as bridging therapies to hematopoietic stem cell transplantation rather than providing durable cures.
For this reason, our current research focuses first on developing safer CAR-T constructs capable of promoting faster recovery of T-cell immune function.
Only after demonstrating meaningful improvements in immune reconstitution would we consider incorporating strategies such as CD5/CD7 dual-target CAR designs to achieve more durable long-term outcomes.
Another challenge involves determining the optimal timing of transplantation. If transplantation is performed too early, residual CD5-positive malignant cells may remain and increase the risk of relapse. If performed too late, complications associated with prolonged T-cell deficiency become increasingly problematic.
Identifying the optimal transplantation window therefore remains a critical unanswered question.
Ultimately, addressing these challenges will require a multidimensional strategy supported by several carefully designed clinical trials.
Looking Forward
The development of NbCD5 CAR-T represents more than a structural refinement of an existing therapy. It reflects a broader effort to improve both efficacy and long-term safety in T-cell malignancies.
By accelerating CAR-T expansion, shortening toxicity duration, and potentially reducing severe infections, this next-generation platform offers a promising approach for patients with limited therapeutic options after CD7 CAR-T failure.
At the same time, the study highlights the next frontier in T-cell immunotherapy: overcoming immune dysfunction, preventing antigen escape, and optimizing integration with transplantation strategies. If these challenges can be addressed successfully, future CAR-T therapies may move beyond serving as bridge therapies and toward delivering durable, long-term disease control.
Expert Profile
Dr. Jing Pan
Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences / Beijing Gobroad Hospital
Associate Chief Physician, MD, PhD in Immunology
Director of the POC Ward, Institute of Hematology and Blood Diseases Hospital
Tenure-Track Associate Professor and PhD Supervisor, Peking Union Medical College
Principal Investigator, State Key Laboratory of Blood and Health
Director, Hematologic Oncology Immunotherapy Department, Beijing Gobroad Hospital
Dr. Pan has long focused on the clinical translation of CAR-T therapy for relapsed and refractory leukemia. Her research has addressed key challenges in T-cell malignancies and post-treatment relapse in B-ALL.
She was the first investigator worldwide to propose and validate donor-derived CD7 CAR-T therapy for relapsed/refractory T-ALL, significantly advancing the clinical translation of CAR-T treatment in this disease. Her work has also pioneered dual-epitope CD5 CAR-T strategies for antigen escape following CD7 CAR-T therapy and sequential CD19/CD22 CAR-T approaches to improve long-term outcomes in relapsed/refractory B-ALL.
Her findings have been published in leading journals including The Lancet Oncology, Journal of Clinical Oncology, Nature Medicine, and Blood, with multiple highly cited publications and inclusion in several international and national treatment guidelines.
