Small Molecule Specific CAR T/CAR NK Cell Therapy for Multiple Myeloma

Abstract

Chimeric antigen receptor (CAR) T cell immunotherapies have achieved durable clinical responses for some patients with hematologic cancers over the last decade. However, relapse rates remain high and patients with solid tumors have not had the clinical benefits that patients with hematologic cancers have had. Several limitations to effective CAR T cell therapy for cancers include uncontrolled immune activity, on-target but off-tumor toxicities, innate and acquired tumor heterogeneity and tumor escape, to name a few. Recently, CAR NK cell therapy has shown promise as an immunotherapy with lower toxicities. Our group engineered small-molecule specific CAR T and CAR NK cells that can be redirected to target various proteins expressed on the tumor surface by co-dosing antibodies specific to those cell surface proteins conjugated to small-molecules. Such binary-activated immune effector cells enable titratable, multiplexable and precise antigen targeting against heterogeneous tumor populations. In multiple myeloma, CAR T cells targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor, class C, group 5, member D (GPRC5D) have each demonstrated substantial initial responses in patients with advanced disease. However, BCMA- and GPRC5D-negative relapses indicate a need for alternate antigen targets and new treatment modalities for combination therapies to multiplex the response in low-antigen-density reservoirs of relapse. CD138 (Syndecan-1, SDC1), a commonly used plasma cell (PC) marker and an established multiple myeloma antigen, has been identified in preclinical studies as a potent antigen target for monoclonal antibody (mAb)-based immunotherapy for all stages of multiple myeloma. In this thesis, I demonstrated the feasibility of targeting CD138 on multiple myeloma cells with fluorescein conjugated anti-CD138 antibody and small molecule-specific CAR T cells and CAR NK cells. I characterized the specificity and efficacy of small molecule-specific CAR T cells and CAR NK cells in comparison with conventional anti-CD138 CAR T cells and CAR NK cells. I elucidated the differential cytotoxic kinetics of small-molecule specific CAR T cells and CAR NK cells. These findings will accelerate the development of a redirectable, multiplexable CAR system to treat advanced and refractory multiple myeloma.