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. ORCID: https://orcid.org/0000-0003-0028-9396, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, 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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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
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:	02 Dec 2024 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/106779

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