Tang and Zheng et al. developed a drug delivery system comprising a protein of interest (e.g., cytokine) cross-linked with a reversible disulfide linker, forming a nanogel that is anchored to the T cell surface via CD45, which allows for prolonged surface retention. Upon TCR stimulation, T cells increase cell surface reduction activity, which triggers the release of the protein via cross-link cleavage. In vivo, adoptive transfer of T cells with IL-15-loaded nanogels significantly slowed tumor growth, improved survival, and lessened toxicity (due to tumor-targeted release) in mice with melanoma, compared to transfer of T cells combined with free IL-15.
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.