Title: “Engineering Split Chimeric Antigen Receptor (CAR) for Adoptive Natural Killer Cell Therapy”
Wilson Wong, PhD – BME (Advisor, Chair)
Hadi Nia, PhD – BME
Andrew Emili, PhD – Biochemistry/BME
Gustavo Mostoslavsky, MD, PhD – BUMC Microbiology
Chimeric antigen receptor (CAR)-T cells have emerged as an effective cell-based therapy for cancer treatment, and the recent FDA approval of CAR-T therapy for the treatment of acute lymphoblastic leukemia has further established its potency. Despite CAR-T’s clinical successes, the skyrocketing costs of these highly personalized therapies can hamper access to this breakthrough technology. To help mitigate these costs, allogenic, off-the-shelf CAR-T cells have been proposed as a more general treatment amenable to mass production. The split, universal, and programmable (SUPRA) CAR system holds the potential to enhance generalized, adaptable CAR-based therapies by allowing a single effector cell line expressing a universal CAR to target multiple unique cancers by exogenous addition of adaptor proteins interfacing the target with the CAR. Additionally, substituting NK cells for T cells may offer another attractive off-the shelf-CAR therapy, as allogenic, unmodified donor NK cells can be used unlike allogenic T cells which need to be tweaked by deleting the TCR. However, it is currently difficult to produce CAR-NK cells with high purity. Through this proposal, I seek to expand the territory of CAR-NK therapy and drive the field of CAR-based therapy toward a general, cost effective treatment model. To achieve this, I will 1) apply the selective proliferation method using artificial antigen presenting cells for CAR-NK, 2) develop a NOT-gate for CAR-NK cells for better target specificity, 3) enhance the activity of the SUPRA CAR system by testing the efficacy of different protein-protein interaction domains as well as the hinge domains.