Irvine, Darrell JZhang, Angela Qixin2021-11-2220212021-11-162021-11Zhang, Angela Qixin. 2021. Biomaterials-Inspired Advances to CAR T Cell Therapy: Strategies to Recognize Tumors and Enhance T Cell Activity. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.28643907https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37370076Chimeric antigen receptor (CAR) T cell therapy, among other adoptive cell transfer approaches, has emerged as a promising strategy to introduce tumor-specific T cells into patients. CAR T cell therapy, in particular targeting CD19, has had great success in the treatment of hematological malignancies. However, CAR T cell treatment of solid tumors has been limited by several challenges—(1) target antigen selection, complicated by tumor heterogeneity and on- target, off-tumor toxicity; (2) CAR T cell exhaustion, limiting their persistence and function; and (3) interaction with and engagement of the endogenous immune system. This thesis addresses these topics with a biomaterials-centered approach, with the hope of tackling barriers to therapy from several perspectives. Chapter 2 tackles the problem of tumor heterogeneity by developing a strategy to deliver CAR T cell ligands to tumors using the membrane-inserting properties of amphiphile-ligands. We demonstrate that intratumorally- administered amph-ligand labels tumor cell membranes, recruits ligand-specific CAR T cells, and triggers potent antitumor efficacy in both syngeneic and xenograft tumor models. Furthermore, this therapy primes endogenous tumor-specific T cells. In Chapter 3, we apply the amph-ligand approach to vaccine boosting CAR T cells as a potential solution to CAR T cell exhaustion and limitations of CAR T cell manufacturing, and turn to characterization of the vaccine strategy and differences as a result of CAR design. Finally, Chapter 4 describes an approach to recruit endogenous virus-specific T cells to tumors via the delivery of viral peptides to tumors. Taken together, these strategies demonstrate the potential of biomaterials to transform CAR T cell therapy, promoting not only greater response rates and lasting tumor control, but also broadening the number of patients and cancer types that can be treated.application/pdfenadoptive cell therapyantigen heterogeneityCAR T cellintratumoralon-target off-tumor toxicitysolid tumorBioengineeringMedicineMaterials ScienceThesis or Dissertation2021-11-220000-0003-2599-2774