Maciocia, Paul M., Wawrzyniecka, Patrycja A., Philip, Brian, Ricciardelli, Ida, Akarca, Ayse U., Onuoha, Shimobi C., Legut, Mateusz, Cole, David K. ![]() ![]() |
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Abstract
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 β-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.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Publisher: | Nature Publishing Group |
ISSN: | 1078-8956 |
Funders: | Wellcome Trust |
Date of First Compliant Deposit: | 16 January 2018 |
Date of Acceptance: | 18 October 2017 |
Last Modified: | 06 Nov 2023 21:27 |
URI: | https://orca.cardiff.ac.uk/id/eprint/106779 |
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