Engineering genetic thermal switches for remote control of therapeutic T cells
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Adoptive transfer of engineered T cells has shown striking clinical success in treating refractory liquid cancers, yet the inability to spatially regulate T cell activity within select anatomical sites limits efficacy against solid tumors. Inspired by clinical modalities used to heat tumors at depth, we engineer T cells with genetic thermal switches for remote control of transcriptional activity. Synthetic thermal gene switches constructed solely of heat shock elements (HSEs) are tunable and exhibit high specificity to thermal triggers 3-5°C above basal temperature. Using the S7-YB switch, a construct with high specificity for heat induction, we precisely control IL-15 super agonist complex production by donor-derived CAR T cells and preferentially augment T cell proliferation. Together, these factors illustrate the potential of thermal control to augment T cell functions for immunotherapy.