mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors

作者：Henry Withers, Junko Matsuzaki, Mark D. Long, Spencer R. Rosario, Thinle Chodon, Takemasa Tsuji, Richard C. Koya, Li Yan, Jianmin Wang, Tibor Keler, Shashikant Lele, Emese Zsíros, Amit A. Lugade, Alan D. Hutson, Stephanie V. Blank, Nina Bhardwaj, Protul Shrikant, Song Liu, Kunle Odunsi · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010408 · 被引用次数：8 · 研究领域：Immunotherapy and Immune Responses、Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research

Background Perturbation of the mechanistic target of rapamycin (mTOR) pathway can instruct effector versus memory cell fate of tumor antigen-specific T cells in preclinical models. In this study, we sought to understand the impact of rapamycin (sirolimus), an mTOR inhibitor, on reprogramming vaccine-induced T cells to enhance memory responses in patients with solid tumors following completion of their standard therapy. Methods We conducted three phase I clinical trials employing New York esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccination approaches, with or without schedule-varied rapamycin. T cell phenotypes, functions, and Vβ usage in peripheral blood were analyzed to ask whether rapamycin influenced the generation of vaccine-induced T cells with memory attributes. Results The addition of rapamycin to all vaccination approaches was safe and well tolerated. Immediate (days 1–14 postvaccination) or delayed (days 15–28 postvaccination) administration of rapamycin led to a significant increase in the generation of vaccine-induced NY-ESO-1-specific T cells exhibiting central memory phenotypes (CD45RO + CD45RA − CCR7 + ). Moreover, delayed administration resulted in a greater than threefold (p=0.025) and eightfold (p=0.005) increase in the frequency of NY-ESO-1-specific CD4 + T and CD8 + T cells respectively at the time of long-term follow-up, compared with its immediate usage. Conclusion Our novel finding is that delayed administration of rapamycin to patients during th...