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免疫的深刻扩张 称为中性粒细胞髓系衍生抑制细胞(PMN-MDSCs)。这些细胞能有效地抑制 抗肿瘤免疫，因此仍然是以免疫治疗为基础的治疗效果的重大障碍 诱导PMN-MDSCs的癌症模式。小鼠和人乳腺癌包括三重阴性 亚集(TNBC)是一种能有效扩增PMN-MDSCs的肿瘤，其与临床呈负相关。 FDA批准的化疗免疫疗法(CTX-I)方案对特定TNBC亚群的疗效 表达PD-L1。不幸的是，改进用于PMN-MDSC诱发癌症的CTX-I策略的努力通过 以这些细胞为靶点的治疗被证明是不成功的。为此，我们发现我们的临床阶段 一种名为entolimod的免疫疗法药物可刺激抗转移4T1的抗肿瘤免疫，这是一种公认的 扩大PMN-MDSCs的临床前PD-L1 TNBC肿瘤模型。事实上，我们发现恩托莫特能刺激 针对4T1的抗肿瘤免疫部分是通过降低PMN-MDSCs的免疫抑制活性来实现的。 此外，参照用于治疗PD-L1 TNBC患者的CTX-I方案，我们发现 Entolimod增强CTX-I对4T1的抗肿瘤效果，尽管其机制尚未解决。尽管如此 临床前PD-L1TNBC的发现，这些发现在多大程度上转化为人类乳房中的PMN-MDSCs 癌症患者以及这些发现对提高癌症患者CTX-I的影响仍不清楚。因此， 该提案试图揭示内毒素抑制PMN-MDSC活性的机制基础。 在小鼠和人类中，为了推动针对以下癌症的改进CTX-I疗法的设计 包括PD-L1TNBC在内的PMN-MDSC扩增阻碍了疗效。在这方面，entolimod已经 成功完成I期安全试验，累计涉及近200名受试者，其中包括健康 志愿者和癌症患者，从而促进了使用CTX-I方案的恩托莫特的临床翻译。

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.