Optimizing the Efficacy of Adoptive T Cell Transfers and CAR-T Therapies

Abstract

Adoptive T cell therapy (ACT), including chimeric antigen receptor (CAR) T cell therapy, is a type of immunotherapy that typically uses a patient’s own T cells to treat tumors. While ACT has demonstrated tremendous success in hematological malignancies, its efficacy in solid tumors remains limited. Current approaches to improving ACT efficacy focus on developing new CAR vectors that give T cells more advanced properties. However, research and clinical trial data have revealed that the phenotype of the T cell product could also significantly affect its efficacy. This thesis explores two ways to control the phenotypes of T cells to achieve better efficacy against tumors. In the first part, T cells were metabolically labeled with unnatural sugar nanoparticles. Subsequent cytokine conjugation onto T cells allowed them to preferentially differentiate into a type 1 immune response. This method also addressed the obstacle of antigen escape in ACT treatment by activating host immunity and inducing antigen spreading, resulting in a significantly prolonged lifespan in solid tumor models and complete response with only half of the usual curative dose in liquid tumor models. In the second part, the effects of mechanical properties of the extracellular matrix (ECM) on T cells were studied, and its potential applications in ACT product manufacturing were explored. A model ECM based on collagen type I was developed to allow for independent control of matrix stiffness and viscoelasticity, and was subsequently used to generate phenotypically and functionally distinct T cells. T cells harvested from more elastic matrices demonstrated a more effector-like phenotype and better efficacy against tumors in vivo. These two approaches shed light on methods to improve and optimize T cell product manufacturing by controlling the phenotype of the final T cell product.