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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., Competing Interests: M. Birtel reports other from BioNTech Cell and Gene Therapies and grants from BMBF during the conduct of the study; other from BioNTech Cell and Gene Therapy outside the submitted work; in addition, M. Birtel has a patent to PCT/EP2015/073156 pending and issued and a patent to PCT/EP2019/086950 pending. R.-H. Voss reports grants from German Research Foundation (DFG) and Federal Ministry of Education and Research (BMBF) during the conduct of the study; in addition, R.-H. Voss has a licensed patent (WO 2017/059900-A1). K. Reinhard reports grants from BioNTech during the conduct of the study; other from BioNTech outside the submitted work; in addition, K. Reinhard has a patent to PCT/EP2015/060356 pending and issued and a patent to PCT/EP2019/086950 pending. B. Rengstl reports other from BioNTech SE during the conduct of the study; other from BioNTech SE outside the submitted work; in addition, B. Rengstl has a patent to PCT/EP2019/086950 pending. K. Michel reports other from Biontech SE during the conduct of the study; other from Biontech SE outside the submitted work; in addition, K. Michel has a patent to PCT/EP2019/086950 pending. N. Hayduk reports other from Biontech Cell & Gene Therapy during the conduct of the study; other from Biontech Cell & Gene Therapy outside the submitted work; in addition, N. Hayduk has a patent to PCT/EP2019/086950 pending. M. Theobald reports grants from DFG during the conduct of the study; in addition, M. Theobald has a patent to WO2017059900 issued and licensed. P. Oehm reports grants from BMBF and personal fees from BioNTech Cell & Gene Therapies during the conduct of the study; other from BioNTech SE outside the submitted work; in addition, P. Oehm has a patent to PCT/EP2015/056899 pending and issued, a patent to PCT/EP2015/060356 pending and issued, a patent to PCT/EP2015/073156 pending and issued, and a patent to PCT/EP2019/086950 pending. O. Tüereci reports other from BioNTech SE and grants from BMBF during the conduct of the study; other from BioNTech SE outside the submitted work; in addition, O. Tuereci has a patent to PCT/EP2015/056899 pending and issued and a patent to PCT/EP2015/060357 pending and issued; and Managing board members BioNTech SE. U. Sahin reports other from BioNTech SE and grants from BMBF during the conduct of the study; other from BioNTech SE outside the submitted work; in addition, U. Sahin has a patent to PCT/EP2015/056899 pending and issued, a patent to PCT/EP2015/060357 pending and issued, a patent to PCT/EP2015/060356 pending and issued, a patent to PCT/EP2015/073156 pending and issued, and a patent to PCT/EP2019/086950 pending; and Management board member BioNTech SE. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)