Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC.

中文翻译：

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通过全身给药克服胰腺癌瘤内注射 STING 激动剂的挑战


由于瘤内给药的挑战，先天激动剂尚未超越临床前研究，用于大多数肿瘤类型的疗效测试。胰腺导管腺癌 （PDAC） 具有敌对的肿瘤微环境，使 T 细胞功能障碍。先天激动剂治疗可能作为一种 T 细胞启动机制，使 PDAC 对抗 PD-1 抗体 （a-PD-1） 治疗敏感。使用自发形成肝转移的移植小鼠模型、自发发生 PDAC 的基因工程 KPC 小鼠模型和人类患者来源的异种移植模型，我们比较了下一代 STING 激动剂 BMS-986301 的肝内/瘤内和肌肉内全身给药之间的抗肿瘤疗效。流式细胞术、Nanostring 和细胞因子测定用于评估局部和全身免疫反应。本研究表明，通过肌内注射全身施用 STING 激动剂在诱导效应 T 细胞反应和抗肿瘤疗效方面相当于其瘤内注射。与瘤内给药相比，全身给药诱导的 T 细胞耗竭和免疫抑制信号减弱。尽管如此，STING 激动剂的瘤内或全身治疗都与肿瘤浸润 T 细胞上 CTLA-4 表达的增加有关。然而，a-PD-1 和抗 CTLA-4 抗体与全身性 STING 激动剂的组合在 KPC 小鼠自发性 PDAC 模型中证明了抗肿瘤功效。用 PBMC 重构的人类患者来源的异种移植物的小鼠胰腺和肝脏原位模型也表明，瘤内和肌内 STING 激动剂的抗肿瘤和远隔作用是等效的。 综上所述，本研究支持通过全身给药治疗 PDAC 的先天激动剂的临床开发。