Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery
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Author(s)
Tang, Li
Zheng, Yiran
Melo, Mariane Bandeira
Mabardi, Llian
Castaño, Ana P
Xie, Yu-Qing
Li, Na
Kudchodkar, Sagar B
Wong, Hing C
Jeng, Emily K
Date Issued
July 2018
Journal
Nature Biotechnology
Publisher
Nature Publishing Group
Citation
Tang, Li et al. “Enhancing T Cell Therapy through TCR-Signaling-Responsive Nanoparticle Drug Delivery.” Nature Biotechnology 36 (July 2018): 707-716. © 2018 Nature America, Inc., part of Springer Nature
Version
Author's final manuscript
Abstract
Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to ‘backpack’ large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface–conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/nbt.4181
