Modulating T cell Therapies with Biomaterials

Abstract

Adoptive T cell therapy has shown remarkable promise in hematological cancers, but has seen limited efficacy in solid tumors. The efficacy of adoptive T cell therapy in solid tumors can be enhanced by developing strategies that generate the desired populations of T cells in vitro, and maximize their function in vivo. Most approaches aiming to generate various T cell populations in vitro are limited to altering the strength and duration of T cell stimulation, and approaches that can further tune T cell phenotype for a given stimulation regimen could broaden the repertoire of T cells available for therapy. Inspired by the emerging consensus that T cell phenotype and function are inherently linked to their tissue localization, this thesis first presents an approach to generating functionally distinct T cell populations via the physical properties of their surrounding matrix, by developing a collagen type 1 based extracellular matrix (ECM) that allows for independent tuning of matrix stiffness and viscoelasticity, two features that characterize the mechanical properties of tissues. The engineered ECM was utilized to generate phenotypically and functionally distinct T cell populations from cells that received the same initial stimulation. Even when the desired T cell populations are achieved in vitro, a major drawback with T cell therapy for solid tumors is that the adoptively transferred T cells are administered systemically, and very few systems have attempted to localize and concentrate T cell responses to the tumor site. In addition, while adoptively transferred T cells provide the T cell source needed for immediate tumor debulking, their long-term efficacy can be hindered by their narrow repertoire of antigen recognition, which can result in tumor antigen escape, exhaustion and limited ability for long-term protection. We address these limitations in this thesis by developing a biomaterials-based T cell depot that can be injected at the tumor site to locally concentrate T cells to the tumor. In addition, this depot enhances the efficacy of locally delivered T cells by synergistically generating host T cell populations with a broader repertoire for antigen recognition and an enhanced ability for long-term protection.