为推动我国细胞治疗与免疫治疗领域的创新发展，深入交流关键科学问题，共享最新临床研究进展，以全球视野促进该领域的协同合作与临床转化，由浙江大学、国际临床血液学学会（IACH）、浙江省免疫学会及浙江省抗癌协会联合主办，浙江大学医学院附属第一医院与良渚实验室联合承办的2025国际细胞治疗与免疫治疗大会（CTI 2025），于2025年11月13-16日在浙江杭州召开。会议期间，《肿瘤瞭望-血液时讯》特邀加拿大多伦多大学医疗网络玛格丽特公主癌症中心、香港肿瘤及免疫学中心Tak W. Mak教授，围绕TCR临床转化的挑战与策略以及TCR与新兴免疫治疗模式协同前景等核心议题展开深度对话，旨在为临床实践提供前沿视角与国际参考。
Q1
根据您的经验，在验证广泛肿瘤反应性TCR用于临床转化时遇到了哪些挑战？
Tak W. Mak教授：广谱肿瘤反应性T细胞受体（TCRs）临床转化验证过程中面临的挑战具有多面性。从科学层面而言，核心挑战在于筛选出理想靶点，该靶点需既能特异性识别并攻击肿瘤细胞，又不会对机体正常组织细胞造成损伤，而人乳头瘤病毒等病毒相关靶点在此方面具有潜在应用价值。
另一重要挑战为成本问题，当前该类疗法的研发及应用成本较高，但随着技术的不断发展，有望从细胞疗法逐步转向双特异性T细胞衔接器（BiTE）技术，即通过双特异性靶向策略，可能借助TCR受体并将其与抗CD3抗体连接，以招募T细胞发挥抗肿瘤作用。
此外，肿瘤细胞常通过自身突变逃避抗原呈递过程，这也是临床转化中需应对的关键问题，对应的解决方案为联合使用针对不同人类白细胞抗原（HLAs）的多种TCRs。
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
您如何设想TCR测序与免疫肿瘤学研究的整合在未来几年内演变，以增强广泛反应性T细胞受体的鉴定？
Tak W. Mak教授：在规避人类白细胞抗原（HLA）限制方面，γδ T细胞可能是一个有前景的方向，因为约80%的γδ T细胞不依赖于HLA I类或II类分子呈递抗原，这为相关免疫治疗策略提供了新的可能性。
从对超过25种恶性肿瘤及其对免疫检查点抑制剂反应的分析结果来看，应答持久且效果显著的患者群体通常伴有γδ T细胞以及CD4+和CD8+ T细胞的共同存在。
进一步而言，在CAR-T免疫疗法或抗体药物偶联物（ADC）治疗过程中可以观察到，γδ T细胞与αβ T细胞实际上也参与其中，不仅协同维持疾病缓解状态，还能凭借其自身固有的抗肿瘤特性，在不依赖于CAR或ADC的情况下持续对肿瘤发起攻击，这一现象提示多亚型T细胞的协同作用可能成为优化免疫治疗的重要方向。
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
展望未来，您认为广泛反应性TCR研究与新兴的免疫治疗技术之间的协同潜力如何？在国际合作或产业转化层面，哪些研究方向最值得优先推进？
Tak W. Mak教授：当前，针对白血病、淋巴瘤及骨髓瘤的CAR-T细胞疗法已积累充分的研究基础，而免疫治疗领域亟待突破的关键在于实体瘤靶点的探索——这已成为制约免疫治疗临床获益的核心瓶颈。现有免疫检查点抑制剂，如PD-1/PD-L1联合CTLA-4或LAG3方案，虽能带来一定疗效增益，但尚未实现突破性进展。在此背景下，TCR与ADC的联合应用策略展现出显著潜力，有望通过协同作用机制突破传统免疫治疗的局限性，为实体瘤治疗开辟新的研究方向。
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.
专家简介
Tak W. Mak 教授
加拿大多伦多大学医疗网络玛格丽特公主癌症中心、香港肿瘤及免疫学中心
自 1984 年起，担任多伦多大学（University of Toronto）医学物理（Medical Biophysics）与免疫学（Immunology）系教授。
Princess Margaret 癌症中心（Princess Margaret Cancer Centre） / 大学医疗网络(UHN)：高级科学家（Senior Scientist）
担任 Campbell 家族乳腺癌研究所主任（Director）。
2002年当选美国国家科学院 (National Academy of Sciences，免疫学方向）
他与团队共同发现了人类 T 细胞受体 (T-cell receptor, TCR) 的基因，这一发现是现代免疫学和癌症免疫疗法的基础。