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Safety and efficacy of Tet-regulated IL-12 expression in cancer-specific T cells

Alsaieedi, A; Holler, A; Velica, P; Bendle, G; Stauss, HJ; (2019) Safety and efficacy of Tet-regulated IL-12 expression in cancer-specific T cells. Oncoimmunology , 8 (3) , Article 1542917. 10.1080/2162402X.2018.1542917. Green open access

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Abstract

We explored whether engineering of T cell specificity and effector function improves immunotherapy of solid tumors. Although IL-12 can enhance cancer immunity, a strategy of safe IL-12 delivery without toxicity is currently lacking. We engineered T cells to express IL-12 controlled by the NFAT promoter responsive to TCR stimulation, or by the Tet-On promoter responsive to doxycycline. In vivo, NFAT-engineered T cells caused lethal toxicity, while Tet-engineered T cells were safe in the absence of doxycycline. Combining gene transfer of the melanoma-specific TRP2-TCR with Tet-IL-12 engineering revealed that temporal induction of IL-12 was essential to inhibit the growth of B16F10 melanoma tumors. Induced IL-12 increased the number of tumor-infiltrating T cells and also prevented the down-modulation of the TRP2-TCR and the associated up-regulation of the PD1 marker that was observed in the absence of IL-12. In addition, temporal induction of IL-12 expression also increased the number of plasmacytoid DC in the tumor micro-environment. We show that repeated induction of IL-12 can be used to enhance control of tumor growth without encountering systemic toxicity. The observation that TCR engineering combined with Tet-regulated IL-12 expression can achieve tumor immunity without the side effects that are usually associated with the in vivo use of IL-12 warrants translation of this concept into the clinic.

Type: Article
Title: Safety and efficacy of Tet-regulated IL-12 expression in cancer-specific T cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/2162402X.2018.1542917
Publisher version: https://doi.org/10.1080/2162402X.2018.1542917
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
Keywords: Immunotherapy; TCR; IL-12; T cells; adoptive; engineering; NFAT; Tet
UCL classification: UCL
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 > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10069423
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