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

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.

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Figure 1: Differential detection of TRBC1 but not TRBC2 by JOVI-1 antibody.
Figure 2: Unselected polyclonal and virus-specific T cell populations contain both TRBC1+ and TRBC1 cells.
Figure 3: T cell–derived cell lines and primary T cell malignancies are monoclonally TRBC1+ or TRBC1.
Figure 4: Anti-TRBC1 CAR T cells are effective against and specific for TRBC1+ cell lines and primary T cell malignancies in vitro.
Figure 5: Efficacy and specificity of anti-TRBC1 CAR T cells in Jurkat xenograft mouse models of T cell malignancy.

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Acknowledgements

We would like to thank M. Owen and J. Viney for helpful discussions and H. Stauss (University College London) for provision of the Jurkat TCR-null cell line. The RD114 viral envelope plasmid was a gift from M. Collins (University College London). PeqPam-env, a Gag-Pol expression plasmid, was a gift from E. Vanin (Baylor College of Medicine). P.M.M. was supported by a studentship from Cancer Research UK. M.A. Pule and T.M. were supported by the UK National Institute of Health Research University College London Hospital Biomedical Research Centre. A.U.A. and M.L. are supported by Cancer Research UK. D.K.C. is a Wellcome Trust Career Development Fellow. A.K.S. is a Wellcome Trust Senior Investigator. K.S.P. is the Scientific Director of the National Institute for Health Research Blood and Transplant Unit for stem cell transplantation and immunotherapy. This project was supported by grants from the Kay Kendall Leukaemia Fund (M.A. Pule and P.M.M.; KKL872) and Innovate UK (M.A. Pule and T.M.; 102571).

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P.M.M. designed and performed the experimental work and wrote the manuscript. P.A.W. performed experimental work. B.P. designed and performed in vivo experiments. I.R. generated and tested EBV-specific CTLs. A.U.A. performed immunohistochemistry. S.C.O., D.K.C. and A.K.S. produced soluble TCR molecules, performed surface plasmon resonance analysis and wrote the manuscript. M.L. and A.K.S. identified and characterized iNKTs. G.G., J.S. and M.A. Piris supplied clinical samples. K.S.P. and D.C.L. provided advice and support and wrote the manuscript. T.M. optimized and analyzed immunohistochemical staining and wrote the manuscript. M.A. Pule conceived the idea, designed the experimental work and wrote the manuscript.

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Correspondence to Martin A Pule.

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Competing interests

P.M.M. and M.A. Pule have patent rights for the targeting of TRBC for diagnosis and treatment of T cell malignancies (patent application, World Intellectual Property Organization, WO 2015132598 A1). P.M.M., B.P., S.C.O., K.S.P., D.C.L. and M.A. Pule are shareholders in Autolus, which has licensed anti-TRBC1 technology. S.C.O. and M.A. Pule are also employees of Autolus.

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Maciocia, P., Wawrzyniecka, P., Philip, B. et al. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat Med 23, 1416–1423 (2017). https://doi.org/10.1038/nm.4444

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