Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery

• Main Authors: Tang, Li (Contributor), Zheng, Yiran (Contributor), Melo, Mariane Bandeira (Contributor), Mabardi, Llian (Contributor), Castaño, Ana P (Author), Xie, Yu-Qing (Author), Li, Na (Contributor), Kudchodkar, Sagar B (Author), Wong, Hing C (Author), Jeng, Emily K (Author), Maus, Marcela V (Author), Irvine, Darrell J (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Materials Science and Engineering (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2019-01-18T15:15:02Z.
• Subjects: Article
• Online Access: Get fulltext

 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.