mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors
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...
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BMJ Publishing Group
2025-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/3/e010408.full |
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| author | Li Yan Nina Bhardwaj Tibor Keler Kunle Odunsi Song Liu Junko Matsuzaki Takemasa Tsuji Mark Long Thinle Chodon Emese Zsiros Protul Shrikant Jianming Wang Alan Hutson Stephanie Blank Amit Lugade Richard Koya Spencer R Rosario Henry G Withers Shashikant B Lele |
| author_facet | Li Yan Nina Bhardwaj Tibor Keler Kunle Odunsi Song Liu Junko Matsuzaki Takemasa Tsuji Mark Long Thinle Chodon Emese Zsiros Protul Shrikant Jianming Wang Alan Hutson Stephanie Blank Amit Lugade Richard Koya Spencer R Rosario Henry G Withers Shashikant B Lele |
| author_sort | Li Yan |
| collection | DOAJ |
| description | 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 the contraction phase of vaccine-induced antitumor immune responses was particularly effective in increasing the frequency of memory T cells up to 1 year postvaccination in patients with solid tumors. Further studies are warranted to identify the impact of this approach on the durability of clinical remission.Trial registration number NCT00803569, NCT01536054, NCT01522820. |
| format | Article |
| id | doaj-art-cda3ceebbc7e4c098963c19530b83aac |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-cda3ceebbc7e4c098963c19530b83aac2025-08-20T01:50:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-03-0113310.1136/jitc-2024-010408mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumorsLi Yan0Nina Bhardwaj1Tibor Keler2Kunle Odunsi3Song Liu4Junko Matsuzaki5Takemasa Tsuji6Mark Long7Thinle Chodon8Emese Zsiros9Protul Shrikant10Jianming Wang11Alan Hutson12Stephanie Blank13Amit Lugade14Richard Koya15Spencer R Rosario16Henry G Withers17Shashikant B Lele181 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA9 Icahn School of Medicine at Mount Sinai Tisch Cancer Institute, New York, New York, USA4 R&D, Celldex Therapeutics, Hampton, New Jersey, USA2 Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA1 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA2 Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA2 Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA1 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA3 UChicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA5 Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA10 Department of Immunobiology, The University of Arizona College of Medicine Tucson, Tucson, Arizona, USA1 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA1 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA7 Department of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA6 Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA2 Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA1 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA1 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA5 Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USABackground 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 the contraction phase of vaccine-induced antitumor immune responses was particularly effective in increasing the frequency of memory T cells up to 1 year postvaccination in patients with solid tumors. Further studies are warranted to identify the impact of this approach on the durability of clinical remission.Trial registration number NCT00803569, NCT01536054, NCT01522820.https://jitc.bmj.com/content/13/3/e010408.full |
| spellingShingle | Li Yan Nina Bhardwaj Tibor Keler Kunle Odunsi Song Liu Junko Matsuzaki Takemasa Tsuji Mark Long Thinle Chodon Emese Zsiros Protul Shrikant Jianming Wang Alan Hutson Stephanie Blank Amit Lugade Richard Koya Spencer R Rosario Henry G Withers Shashikant B Lele mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors Journal for ImmunoTherapy of Cancer |
| title | mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors |
| title_full | mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors |
| title_fullStr | mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors |
| title_full_unstemmed | mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors |
| title_short | mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors |
| title_sort | mtor inhibition modulates vaccine induced immune responses to generate memory t cells in patients with solid tumors |
| url | https://jitc.bmj.com/content/13/3/e010408.full |
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