Since the β-chain constant region is encoded by either the TRBC1 or TRBC2 gene, normal T cell populations have a mix of the two genotypes, while T cell malignancies tend to skew toward one or the other. Maciocia et al. confirmed this for many T cell malignancies and took advantage of a TRBC1-specific monoclonal antibody to generate and test proof-of-concept CAR-T cells to demonstrate that such therapy selectively eliminates TRBC1+ malignant and healthy T cells, while leaving the TRBC2+ T cell repertoire intact, preserving cellular immunity.
Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1+ and TRBC2+ compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1+, but not TRBC2+, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.
Author Info: (1) Cancer Institute, University College London, London, UK. (2) Cancer Institute, University College London, London, UK. (3) Cancer Institute, University College London, London, U
Author Info: (1) Cancer Institute, University College London, London, UK. (2) Cancer Institute, University College London, London, UK. (3) Cancer Institute, University College London, London, UK. (4) Institute of Child Health, University College London, London, UK. (5) Cancer Institute, University College London, London, UK. (6) Autolus, Ltd., London, UK. (7) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. (8) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. (9) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. (10) Hematology and Bone Marrow Transplant Units, Papa Giovanni XXIII Hospital, Bergamo, Italy. (11) Department of Anatomy and Cellular Pathology, University of Liege, Liege, Belgium. (12) Department of Pathology, Fundacion Jimenez Diaz, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. (13) Cancer Institute, University College London, London, UK. (14) Cancer Institute, University College London, London, UK. (15) Cancer Institute, University College London, London, UK. (16) Cancer Institute, University College London, London, UK. Autolus, Ltd., London, UK.
