Targeting Universal CAR T cells via antibody-drug conjugates adaptors 4830

Abstract Description Antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) T cells are two powerful cancer immunotherapeutic modalities. ADCs consist of antibodies conjugated to cytotoxic drugs to deliver payloads to antigen positive cells, while CAR T cells have receptors that bind to target antigens on cancer cells, initiating T cell effector functions. However, both therapies face major challenges including resistance to drug payloads and poor antibody internalization for ADCs and inadequate CAR T cell persistence and immunosuppression for CAR T cells. To address these issues, we developed a novel therapy combining the strengths of both approaches. Using our previously developed universal CAR, SNAP-CAR, which binds covalently to anti-tumor antibodies through a benzylguanine (BG) tag, we now created ADC-BG adaptors by conjugating the BG tag to clinical agents mirvetuximab-soravtansine (FOLR1), trastuzumab-emtansine, and trastuzumab deruxtecan (HER2). SNAP-CAR T cells with ADC-BG adaptors showed dose-responsive T cell activation as well as target cell lysis that was more potent than SNAP-CAR T cells paired with the ADC or traditional antibody adaptors. Furthermore, SNAP-CAR T cells incubated with ADC-BG adaptors mediated enhanced bystander tumor cell killing. Finally, in vivo studies in a human ovarian tumor xenograft NSG mouse model revealed enhanced tumor reduction by SNAP-CAR T cells paired with the ADC-BG adaptor. This approach has broad potential as a potent cancer therapy. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)