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Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

Maciocia, Paul M., Wawrzyniecka, Patrycja A., Philip, Brian, Ricciardelli, Ida, Akarca, Ayse U., Onuoha, Shimobi C., Legut, Mateusz, Cole, David K., Sewell, Andrew K., Gritti, Giuseppe, Somja, Joan, Piris, Miguel A., Peggs, Karl S., Linch, David C., Marafioti, Teresa and Pule, Martin A. 2017. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nature Medicine 23 , pp. 1416-1423. 10.1038/nm.4444

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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
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: 19 Jan 2021 19:00

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