PT-112 is a novel platinum-pyrophosphate conjugate under clinical development for cancer therapy. PT-112 mediates cytostatic and cytotoxic effects against a variety of human and mouse cancer cell lines in vitro. The cytotoxic response to PT-112 is associated with the emission of danger signals underpinning the initiation of anticancer immunity, including calreticulin exposure on the surface of dying cells, as well as ATP and HMGB1 secretion. Consistently, mouse cancer cells succumbing to PT-112 in vitro can be used to provide syngeneic, immunocompetent mice with immunological protection against a subsequent challenge with living tumor cells of the same type. Moreover, PT-112 administration synergizes with PD-1 or PD-L1 blockade in the control of mouse cancers in immunologically competent settings, as it simultaneously recruits immune effector cells and depletes immunosuppressive cells in the tumor microenvironment. Finally, PT-112 employed intratumorally in the context of immune checkpoint inhibition initiates a robust immune response that has systemic outreach and limits the growth of untreated, distant lesions. Thus, PT-112 induces the immunogenic demise of cancer cells, and hence stands out as a promising combinatorial partner of immune checkpoint blockers, especially for the treatment of otherwise immunologically cold tumors.

中文翻译：

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PT-112在小鼠肿瘤模型中诱导免疫原性细胞死亡并与免疫检查点阻滞剂协同作用。

PT-112是一种新型的铂-焦磷酸盐偶联物，正在临床开发中用于癌症治疗。PT-112在体外介导针对多种人类和小鼠癌细胞系的细胞生长抑制作用和细胞毒性作用。对PT-112的细胞毒性反应与危险信号的发射有关，这些信号支撑着抗癌免疫力的启动，包括垂死细胞表面上的钙网蛋白暴露以及ATP和HMGB1的分泌。一致地，在体外死于PT-112的小鼠癌细胞可用于为具有免疫保护能力的同基因小鼠提供免疫保护，以防止随后攻击相同类型的活体肿瘤细胞。此外，PT-112的给药与PD-1或PD-L1的阻断作用在免疫学上可以控制小鼠癌症，因为它同时在肿瘤微环境中募集免疫效应细胞并耗尽免疫抑制细胞。最后，在免疫检查点抑制的背景下在肿瘤内使用的PT-112引发了强大的免疫反应，具有全身性免疫功能，并限制了未经治疗的远处病变的生长。因此，PT-112诱导癌细胞的免疫原性死亡，因此作为免疫检查点阻滞剂的有希望的组合伴侣而脱颖而出，特别是在治疗免疫原性较冷的肿瘤方面。