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

Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success, but 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 using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor (TCR) activation. We design cell surface-conjugated NGs that respond to an increase in T cell surface reduction potential upon antigen recognition, limiting drug release to sites of antigen encounter such as the tumor microenvironment. Using NGs carrying an IL-15 superagonist complex, we demonstrate that relative to systemic administration of free cytokines, NG delivery selectively expands T cells 16-fold in tumors, and allows at least 8-fold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enables substantially increased tumor clearance by murine T cell and human CAR-T cell therapy in vivo.