Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2024 May 10;15(1):3933. doi: 10.1038/s41467-024-47692-9.
As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.
作为提高嵌合抗原受体 T 细胞（CART）针对实体瘤治疗成功率的一种策略，我们在此测试了 CART 与 IMSA101 的联合使用，后者是一种新开发的干扰素基因刺激剂（STING）激动剂。在两种同基因肿瘤模型中，当小鼠接受肿瘤内给予的 IMSA101 联合静脉内 CART 输注治疗时，观察到总生存期得到改善。对从肿瘤中分离出的 CART 的转录组分析显示，在联合治疗组中，T 细胞激活水平升高，细胞因子途径特征上调，特别是 IL-18。用 IMSA101 治疗还可检测到血清和肿瘤中 IL-18 水平升高。与此一致的是，在接受联合治疗的小鼠中使用缺乏 IL-18 受体的 CART 会削弱抗肿瘤反应。总之，我们发现 IMSA101 增强了 CART 的功能，这是通过 STING 激动剂诱导的 IL-18 分泌来实现的。
