受光热调控产生免疫调节分子的工程化 CAR-T 细胞瘤内活性增强

Treating solid malignancies with chimeric antigen receptor (CAR) T cells typically results in poor responses. Immunomodulatory biologics delivered systemically can augment the cells' activity, but off-target toxicity narrows the therapeutic window.

Here we show that the activity of intratumoural CAR T cells can be controlled photothermally via synthetic gene switches that trigger the expression of transgenes in response to mild temperature elevations (to 40-42 C). In vitro, heating engineered primary human T cells for 15-30 min led to over 60-fold-higher expression of a reporter transgene without affecting the cells' proliferation, migration and cytotoxicity. In mice, CAR T cells photothermally heated via gold nanorods produced a transgene only within the tumours.

In mouse models of adoptive transfer, the systemic delivery of CAR T cells followed by intratumoural production, under photothermal control, of an interleukin-15 superagonist or a bispecific T cell engager bearing an NKG2D receptor redirecting T cells against NKG2D ligands enhanced antitumour activity and mitigated antigen escape. Localized photothermal control of the activity of engineered T cells may enhance their safety and efficacy.