Materials to enable and enhance T-cell immunotherapies

Abstract

Immunotherapies involving engineered T cells have shown remarkable clinical outcomes for the treatment of cancer, particularly hematological malignancies, such as leukemia and lymphoma. However, several barriers need to be overcome before these adoptive cellular therapies can be accessed by a broader patient population and be applied to other cancers. Currently, the lack of control over the quality of T-cell products limits the cells’ intrinsic ability to proliferate, persist, and effectively kill tumor cells in vivo. This can, in part, be attributed to the synthetic materials used to mediate T-cell activation, a key step in therapeutic T-cell production. Conventional materials fail to recapitulate key features of physiological T-cell activation, resulting in poor control over T-cell quality and yield.

In this thesis, we address these challenges by developing material scaffolds that mimic physiological antigen presentation and provide precise control over T-cell activation to create and manipulate T cells ex vivo and in vivo. First, we design and characterize the material scaffolds, defining and optimizing key parameters for ex vivo human T-cell activation and expansion. The materials are used to improve T-cell immunotherapies in two approaches: (1) by engineering the materials to tune T cell-intrinsic attributes to enhance therapeutic T-cell products, and (2) by using the materials as an injectable scaffold niche for local T-cell stimulation, to boost systemic antitumor responses of prior-administered T-cell immunotherapies. Together, this thesis describes a materials-based approach to manipulate T-cell biology, enabling the controlled manufacture of high-quality T-cell products ex vivo and the enhancement of their therapeutic functions in vivo.