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

Maciocia, PM; Wawrzyniecka, PA; Akarca, AU; Philip, B; Ricciardelli, I; Somja, J; Onuoha, SC; ... Pule, MA; + view all (2017) Targeting T-cell receptor β-constant region for immunotherapy of T-cell malignancies. Nature Medicine , 23 (12) pp. 1416-1423. 10.1038/nm.4444. Green open access

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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.

Type: Article
Title: Targeting T-cell receptor β-constant region for immunotherapy of T-cell malignancies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/nm.4444
Publisher version: https://doi.org/10.1038/nm.4444
Language: English
Additional information: This version is the author accepted manuscript/version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Acute lymphocytic leukaemia, Cancer immunotherapy, T-cell lymphoma, Translational research
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10038778
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