BME PhD Dissertation Defense: Sarah Catherine Adams

Title: "Local delivery of small molecules for switch CAR T cells to improve safety and efficacy in solid tumors"

Advisory Committee: Wilson Wong, PhD – BME (Co-Research Advisor) Mark Grinstaff, PhD – BME (Co-Research Advisor) Timothy O’Shea, PhD – BME, MSE (Chair) Ahmad (Mo) Khalil, PhD – BME Dave Sherr, PhD – Environmental Health

Abstract: While Chimeric Antigen Receptor (CAR) T cell therapies have massively improved treatment outcomes for lymphoma and multiple myeloma, many challenges remain for improving the efficacy and safety of CAR therapies. Specifically, treatment related adverse events are still a massive challenge for patients and clinicians with over 60% of CAR T cell patients in clinical trials experiencing a grade 3 or higher adverse event. One approach to mitigate these side effects is small molecule controlled gene circuits. Several groups have explored different drug inducible CAR circuits but deliver the drug at high concentrations systemically. Meanwhile biomaterials enable localized delivery of therapeutics to further regulate the spatial temporal profile of a small molecule or protein. To leverage these inducible gene circuits and biomaterials, we developed electrospun, hydrophobic nanofiber meshes that deliver small molecules for local CAR T cell activation. We demonstrate improved safety and efficacy in a model of mesothelioma without evidence of CAR T cell toxicity. Together, these results demonstrate a novel and robust approach to improve safety and efficacy in local cancer therapy.