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

开发基于 TLR5 激动剂的方法，通过调节免疫抑制网络来促进化疗免疫治疗

• 批准号: 10543545
• 负责人: Craig M. Brackett
• 金额: $ 19.27万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-23 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543545
• 关键词: 4T1; Abraxane; Adjuvant; Agonist; Biotin; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Reprogramming; Cells; Clinical; Clinical Protocols; Cytoplasmic Receptors; Data; Development; Diagnosis; Disease; Engineering; Exposure to; FDA approved; Female; Flagellin; Flow Cytometry; Genetic; Goals; Grant; Human; Immune; Immuno-Chemotherapy; Immunosuppression; Immunotherapy; Implant; Inflammasome; Knowledge; Link; Malignant Neoplasms; Measures; Mediating; Modality; Modeling; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Phase; Phenotype; Pre-Clinical Model; Protocols documentation; Publishing; Role; Safety; Salmonella; Septic Shock; Signal Pathway; Signal Transduction; Sorting; Spleen; Syndrome; T-Cell Proliferation; T-Lymphocyte; TLR5 gene; Therapeutic Intervention; Time; Translating; Tumor Immunity; Work; anti-PD-1; anti-PD-L1; blood treatment; cancer therapy; carcinogenesis; clinical translation; design; healthy volunteer; immune checkpoint blockade; improved; innovation; malignant breast neoplasm; mammary; monocyte; neutrophil; novel; novel strategies; pharmacologic; pre-clinical; programmed cell death ligand 1; programs; receptor; therapeutic target; triple-negative invasive breast carcinoma; tumor; volunteer

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.

抽象的 某些小鼠和人类癌症会刺激一种高度免疫抑制性免疫的深度扩展 细胞称为多形核骨髓源性抑制细胞（PMN-MDSC）。这些细胞有效抑制 抗肿瘤免疫，因此仍然是免疫疗法疗效的重大障碍 诱导 PMN-MDSC 的癌症治疗方式。小鼠和人类乳腺癌，包括三阴性乳腺癌 亚型（TNBC）是一种能够有效扩增 PMN-MDSC 的癌症，这与临床表现呈负相关。 FDA 批准的针对特定 TNBC 子集的化学免疫治疗 (CTx-I) 方案的结果 表达 PD-L1。不幸的是，改善 CTx-I 策略以预防 PMN-MDSC 诱发癌症的努力 针对这些细胞的治疗已被证明是不成功的。为此，我们发现我们的临床阶段 称为恩托莫德的免疫治疗药物可刺激针对转移性 4T1 的抗肿瘤免疫，这是一种公认​​的 扩展 PMN-MDSC 的临床前 PD-L1+ TNBC 肿瘤模型。事实上，我们发现恩托莫德会刺激 针对 4T1 的抗肿瘤免疫部分是通过降低 PMN-MDSC 的免疫抑制活性来实现的。 此外，根据用于治疗 PD-L1+ TNBC 患者的 CTx-I 方案，我们发现 恩托莫德增强了 CTx-I 对抗 4T1 的抗肿瘤功效，尽管是通过尚未解决的机制实现的。尽管有这些 临床前 PD-L1+ TNBC 的发现，这些发现在多大程度上转化为乳腺中的人类 PMN-MDSC 癌症患者以及这些发现对癌症患者增强 CTx-I 的影响仍不清楚。因此， 该提案旨在揭示 enolimod 抑制 PMN-MDSC 活性的机制基础 在小鼠和人类中进行研究，以推动针对那些癌症的改进的 CTx-I 疗法的设计 功效受到包括 PD-L1+ TNBC 在内的 PMN-MDSC 扩增的阻碍。而在这方面，恩托莫德 成功完成I期安全性试验，累计涉及健康受试者近200人 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。