To advance innovation in China’s cell and immunotherapy landscape, deepen exchanges on key scientific questions, and share the latest clinical research progress, the 2025 International Cell and Immunotherapy Conference (CTI 2025)—jointly organized by Zhejiang University, the International Academy for Clinical Hematology (IACH), the Zhejiang Society of Immunology, and the Zhejiang Anti-Cancer Association, and co-hosted by the First Affiliated Hospital of Zhejiang University School of Medicine and the Liangzhu Laboratory—was held in Hangzhou, Zhejiang, from November 13 to 16, 2025. During the conference, Hematology Frontier – Oncology Frontier invited Prof. Tak W. Mak from the Princess Margaret Cancer Centre, University Health Network, Toronto, and the Hong Kong Center for Cancer and Immunology, for an in-depth conversation centered on the major challenges and strategic considerations in translating TCR therapies to the clinic, as well as the prospects for TCR-based approaches to integrate with emerging immunotherapeutic modalities. The discussion aims to offer clinicians cutting-edge perspectives and international insights to inform practice.
Q1、In your experience, what challenges have you encountered in validating broadly tumor-reactive TCRs for clinical translation?
I think the challenges are multiple. Scientifically, the challenge is to identify a target which attacks the tumor and at the same time does not attack one’s own body. And I think in that context, viral targets like human papillomaviruses and other viruses would be ideal. Another challenge is the cost; the cost at this particular time is very high, but I guess in time one would be able to transition from cell therapy to a BiTE, which is bispecific targeting, and this could involve using the TCR receptor and linking it to an anti-CD3 to bring in T cells. So I think those are the two main ones. And the last one is that tumors ordinarily have existing mutations to evade antigen presentation, and so the solution would be to combine different TCRs against different HLAs.
Q2、How do you envision the integration of TCR sequencing and immuno-oncology research evolving to enhance the identification of broadly reactive T cell receptors in the coming years?
Well, I think that in terms of overcoming HLA restriction, gamma delta T cells would be a possibility. Because the majority (80%) of gamma delta T cells are independent of HLA class I or class II. It is still something for us to look forward to. When examining over 25 different malignancies and their responses to immune checkpoints, the answer is very clear: those that achieved durable responses are mostly those with gamma delta T cells, as well as CD4+ and CD8+ T cells. So in a way, in the context of CAR-T immunotherapy or antibody-drug conjugates (ADCs), we observe that T cells—including gamma delta and alpha beta T cells—do participate to maintain remission as well as continue to attack the tumor through their intrinsic properties, independent of CAR-T cells or ADCs.
Q3、Looking ahead, how do you foresee the synergy between broadly reactive TCR research and emerging immunotherapy modalities ? From a global collaboration or translational standpoint, which research areas should be prioritized?
I think there are enough activities in CAR-T therapy for leukemia, lymphomas, and myelomas. I think it’s really time for us to start thinking about what the targets in solid tumors are, because ultimately, this is the bottleneck in immunotherapy. We know that checkpoint blockade strategies beyond PD-1/PD-L1 plus CTLA-4 or PD-1/PD-L1 plus LAG3 offer only marginal additional benefits, but there are no real breakthroughs beyond that. And I think the idea of combining TCR with antibody-drug conjugates (ADCs) is a promising possibility.
【Expert Biography】 — Tak W. Mak
Since 1984, Professor Tak W. Mak has been a faculty member in the Departments of Medical Biophysics and Immunology at the University of Toronto. He is a Senior Scientist at the Princess Margaret Cancer Centre / University Health Network (UHN) and Director of the Campbell Family Institute for Breast Cancer Research.
In 2002, he was elected to the U.S. National Academy of Sciences (Immunology section).
Professor Mak and his team discovered the genes encoding the human T-cell receptor (TCR), a landmark finding that laid the foundation for modern immunology and cancer immunotherapy.
