Development of TLR5 agonist based approaches to boost chemo-immunotherapy by modulating immunosuppressive networks

摘要 某些小鼠和人类癌症刺激一种高度免疫抑制的免疫系统的显著扩张， 这种细胞称为多形核白细胞髓源性抑制细胞（PMN-MDSC）。这些细胞能有效抑制 因此仍然是基于免疫疗法的治疗功效的显著障碍 用于诱导PMN-MDSC的癌症的模式。小鼠和人类乳腺癌，包括三阴性 TNBC是一种有效扩增PMN-MDSC的癌症，其与临床表现负相关。 FDA批准的用于特定TNBC子集的化学免疫疗法（CTx-I）方案的结果， 表达PD-L1。不幸的是，通过以下方法改善用于PMN-MDSC诱导癌症的CTx-I策略的努力是不成功的： 治疗靶向这些细胞已被证明是不成功的。为此，我们发现我们的临床阶段 一种名为恩托莫德的免疫治疗药物刺激针对转移性4T1的抗肿瘤免疫， 扩增PMN-MDSC的临床前PD-L1 + TNBC肿瘤模型。事实上，我们发现恩托莫德 PMN-MDSC的免疫抑制活性部分地通过减少PMN-MDSC的免疫抑制活性来增强针对4T1的抗肿瘤免疫力。 此外，与用于治疗诊断为PD-L1 + TNBC的患者的CTx-I方案相呼应，我们发现， 恩托莫德增强了CTx-I针对4T1的抗肿瘤功效，尽管是通过未解决的机制。尽管有这些 临床前PD-L1 + TNBC中的发现，这些发现在多大程度上转化为乳腺癌中的人PMN-MDSC 癌症患者以及这些发现对增强癌症患者CTx-I的影响仍不清楚。因此，在本发明中， 该提案旨在揭示恩托莫德抑制PMN-MDSC活动的机制基础 在小鼠和人类中，为了推动针对那些癌症的改进CTx-I疗法的设计， 有效性受到包括PD-L1 + TNBC的PMN-MDSC扩增的阻碍。在这方面，恩托莫德 成功完成的I期安全性试验，累计涉及近200例受试者，包括健康受试者 志愿者和癌症患者，从而促进恩托莫德与CTx-I方案的临床转化。

ABSTRACT Certain mouse and human cancers stimulate profound expansion of a type of highly immunosuppressive immune cell called polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These cells potently inhibit antitumor immunity and thus remain a significant barrier to the efficacy of immunotherapy-based treatment modalities for cancers that induce PMN-MDSCs. Mouse and human breast cancer including the triple negative subset (TNBC) is one such cancer that efficiently expands PMN-MDSCs, which negatively correlates with clinical outcomes in FDA-approved chemo-immunotherapy (CTx-I) protocols for a particular TNBC subset that expresses PD-L1. Unfortunately, efforts to improve CTx-I strategies for PMN-MDSC inducing cancers by therapeutically targeting these cells have proven unsuccessful. To this end, we found that our clinical-stage immunotherapy drug called entolimod stimulates antitumor immunity against metastatic 4T1, a well-recognized pre-clinical PD-L1+ TNBC tumor model that expands PMN-MDSCs. In fact, we found that entolimod stimulates antitumor immunity against 4T1 in part by diminishing the immunosuppressive activity of PMN-MDSCs. Moreover, mirroring the CTx-I protocols used to treat patients diagnosed with PD-L1+ TNBC, we found that entolimod boosts antitumor efficacy of CTx-I against 4T1, albeit, through unresolved mechanisms. Despite these findings in pre-clinical PD-L1+ TNBC, to what extent these findings translate to human PMN-MDSCs in breast cancer patients and implications of these findings for boosting CTx-I in cancer patients remain unclear. Thus, this proposal seeks to uncover the mechanistic underpinnings by which entolimod dampens PMN-MDSC activity in both mice and humans in order to fuel the design of improved CTx-I therapies for those cancers in which efficacy is hindered by PMN-MDSC expansion including PD-L1+ TNBC. And in this regard, entolimod has successfully completed Phase I safety trials cumulatively involving nearly 200 subjects including healthy volunteers and cancer patients thus facilitating the clinical translation of entolimod with CTx-I protocols.