论文
论文标题：Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control
作者：Miller, Ian C., Zamat, Ali, Sun, Lee-Kai, Phuengkham, Hathaichanok, Harris, Adrian M., Gamboa, Lena, Yang, Jason, Murad, John P., Priceman, Saul J., Kwong, Gabriel A.
期刊：Nature Biomedical Engineering
发表时间：2021/08/12
数字识别码：10.1038/s41551-021-00781-2
摘要：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.
[1] Miller, I.C., Zamat, A., Sun, LK. et al. Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00781-2
