Yu-Qing Xie1 Lixia Wei1 Yu Zhao1 Li Tang1

1, EPFL, Lausanne, , Switzerland

Adoptive cell therapy (ACT) employing antigen-specific T-cells has elicited dramatic clinical responses in leukemia and a subset of melanoma patients. However, strategies to safely and effectively augment T-cell infiltration and function in solid tumors remain of great interest. Our laboratory aims to enhance adoptive T-cell therapy and other cancer immunotherapies through responsive nanoparticle drug delivery. Here we describe a strategy to enhance the tumor-infiltration and function of transferred T-cells by spatiotemporally controlled delivery of immunomodulators. Responsive protein nanogels (NGs) containing large quantities of immunomodulatory drugs are designed and synthesized to release the drugs in response to the reductive environment specific in tumor tissue or on T-cell surface. We show that T-cells increase their cell surface reduction potential upon activation, which we exploit through the design of cell surface-bound NGs that disassemble to release protein cargos in response to this change in the local reductive environment following T-cell receptor (TCR) triggering. The T-cell surface-bound NGs selectively release adjuvant drugs in response to TCR activation, focusing drug release in sites of antigen encounter such as the tumor microenvironment. Using an IL-15 superagonist complex as a candidate adjuvant drug cargo, we demonstrate that relative to systemic administration of free cytokines, NG delivery selectively expands adoptively transferred T-cells 16-fold in tumors, and allows at least 8-fold higher doses of cytokine to be administered without toxicity, leading to substantially increased anti-tumor efficacy and safety. This strategy provides a general approach to augment the function of cell therapies by linking drug release to cell function in vivo.