To address unmet needs of CAR T cell therapy for solid tumors, Birtel, Voss et al, designed a novel heterodimeric TCR-like CAR (TCAR) that recruited and signaled through the endogenous CD3 complex for T cell functions. The TCAR exhibited highly sensitive antigen recognition in vitro, and its function and persistence were further boosted by providing costimulation. In a syngeneic mouse model, the combination of TCARs with a vaccine (CARVAC) designed for antigen-specific expansion of CAR T cells in vivo promoted highly controlled T cell expansion, significantly delayed tumor growth, and prolonged survival, suggesting TCARs could offer an alternative to second generation CARs.
Contributed by Katherine Turner
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.
Author Info: (1) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. Biopharmaceutical New Technologies (BioN
Author Info: (1) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (2) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. Department of Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University, Mainz, Germany. (3) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (4) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (5) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (6) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (7) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (8) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. (9) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. (10) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. (11) Department of Hematology, Oncology, and Pneumology, University Cancer Center (UCT), University Medical Center (UMC) of Johannes Gutenberg University, Mainz, Germany. (12) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (13) Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. (14) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH (non-profit), Mainz, Germany. Biopharmaceutical New Technologies (BioNTech) Corporation, BioNTech Cell & Gene Therapies GmbH, Mainz, Germany. Department of Research Center for Immunotherapy (FZI), University Medical Center (UMC) of the Johannes Gutenberg University, Mainz, Germany.
