PT  - JOURNAL ARTICLE
AU  - Ian C. Miller
AU  - Lee-Kai Sun
AU  - Adrian M. Harris
AU  - Lena Gamboa
AU  - Ali Zamat
AU  - Gabriel A. Kwong
TI  - Remote control of CAR T cell therapies by thermal targeting
AID  - 10.1101/2020.04.26.062703
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.26.062703
4099  - http://biorxiv.org/content/early/2020/05/07/2020.04.26.062703.short
4100  - http://biorxiv.org/content/early/2020/05/07/2020.04.26.062703.full
AB  - The limited ability to control anti-tumor activity within tumor sites contributes to poor CAR T cell responses against solid malignancies. Systemic delivery of biologic drugs such as cytokines can augment CAR T cell activity despite off-target toxicity in healthy tissues that narrows their therapeutic window. Here we develop a platform for remote control of CAR T therapies by thermal targeting. To enable CAR T cells to respond to heat, we construct synthetic thermal gene switches that trigger expression of transgenes in response to mild elevations in local temperature (40–42 °C) but not to orthogonal cellular stresses such as hypoxia. We show that short pulses of heat (15–30 min) lead to more than 60-fold increases in gene expression without affecting key T cell functions including proliferation, migration, and cytotoxicity. We demonstrate thermal control of broad classes of immunostimulatory agents including CARs, Bispecific T cell Engagers (BiTEs), and cytokine superagonists to enhance proliferation and cell targeting. In mouse models of adoptive transfer, photothermal targeting of intratumoral CAR T cells to control the production of an IL-15 superagonist significantly enhances anti-tumor activity and overall survival. We envision that thermal targeting could improve the safety and efficacy of next-generation therapies by allowing remote control of CAR T cell activity.Competing Interest StatementI.C.M., L.G., and G.A.K. are listed as inventors on a patent application pertaining to the results of this paper.