ABSTRACT
Chimeric antigen receptor (CAR) T cells are efficacious in patients with B-cell malignancies, while their activity is limited in patients with solid tumors. We developed a novel heterodimeric TCR-like CAR (TCAR) designed to achieve optimal chain pairing and integration into the T-cell CD3 signaling complex. The TCAR mediated high antigen sensitivity and potent antigen-specific T-cell effector functions in short-term in vitro assays. Both persistence and functionality of TCAR T cells were augmented by provision of costimulatory signals, which improved proliferation in vitro and in vivo. Combination with a nanoparticulate RNA vaccine, developed for in vivo expansion of CAR T cells, promoted tightly controlled expansion, survival, and antitumor efficacy of TCAR T cells in vivo. Significance: A novel TCAR is tightly controlled by RNA vaccine-mediated costimulation and may provide an alternative to second-generation CARs for the treatment of solid tumors.
Subject(s)
Immunotherapy, Adoptive , Neoplasms , mRNA Vaccines , Humans , T-Lymphocytes , Receptors, Chimeric Antigen , CD3 Complex , Cell Proliferation , mRNA Vaccines/immunology , Neoplasms/therapy , Cancer Vaccines/therapeutic use , Animals , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Female , Cell Line, Tumor , Xenograft Model Antitumor AssaysABSTRACT
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 nonpersistence 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 antigen-presenting 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 subtherapeutic CAR-T cell doses.
