The Tang lab’s research focuses on establishing detailed understanding of the interactions between synthetic biomaterials and the immune system, and precisely controlling the immune response using engineered intelligent biomaterials in order to develop effective novel immunotherapies for cancer, infectious diseases and autoimmune disorders. We leverage the power of state of the art synthetic chemistry, materials science and nanotechnology to advance the diagnosis and therapy of human diseases by modulating the immune system with smart biomaterials. In this talk, I will present our recent efforts in enhancing adoptive T-cell therapy through T-cell receptor (TCR) signaling-responsive nanoparticle drug delivery. 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 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 adjuvant drugs in response to TCR activation, focusing drug release in sites of antigen encounter such as the tumor microenvironment. We show that T-cells increase their cell surface reduction potential upon activation, which we exploit through the design of cell surface-conjugated NGs that disassemble to release protein cargos in response to this change in the local reductive environment following TCR triggering. 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 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. This strategy provides a general approach to augment the function of cell therapies by linking drug release to cell function in vivo.

Enhancing cancer immunotherapy using responsive biomaterials

253rd National Meeting (2017)

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