High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Abstract

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1_157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

Keywords

cytokine-activated T cells / high-affinity T cell receptor / cancer immunotherapy / TCR-CAT

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Acknowledgements

This study was supported by the Sciences and Technology Program of Guangzhou (No. 201504010016); the National Key R&D program (No. 2016YFC1303404); and the Sciences and Technology Program of Guangzhou (No. 201704020220). The study was also sponsored by the CAS-TWAS President’s PhD Fellowship Program awarded to Synat Kang.

Compliance with ethics guidelines

Synat Kang, Yanyan Li, Yifeng Bao, and Yi Li declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all healthy donors for inclusion in the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-018-0677-1 and is accessible for authorized users.

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2019 The Author(s) 2019. This article is published with open access at link.springer.com and journal.hep.com.cn