Reinhard, Rengstl, and Oehm et al. identified the oncofetal membrane protein claudin 6 (CLDN 6) as a potential CAR T cell target, expressed in certain solid tumors but not in healthy adult tissue. CLDN6-CAR T cells specifically lysed CLDN6+ tumor cells in vitro and regressed xenograft tumors in vivo. A liposomal CLDN6-RNA vaccine targeted and expressed CLDN6 on APCs, boosting proliferation, effector function, and memory differentiation of transferred CLDN6-CAR T cells. The vaccine together with subtherapeutic levels of CAR T cells regressed CLDN6+ solid tumors and maintained CAR T cell persistence when administered in multiple doses.
Contributed by Alex Najibi
Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet their application for solid tumors has challenges that include limited cancer-specific targets and non-persistence of adoptively transferred CAR-T cells. Here we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors, and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident dendritic cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at sub-therapeutic CAR-T cell doses.