Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer

开发针对三阴性乳腺癌的新型免疫治疗平台

• 批准号: 10287834
• 负责人: Scott I. Abrams
• 金额: $ 23.59万
• 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: 2021-08-06 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287834
• 关键词: 4T1; Abraxane; Adjuvant; Advanced Malignant Neoplasm; Agonist; Breast Cancer Model; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; Clinic; Clinical; Data; Development; Disease; ERBB2 gene; Elements; Engineering; Enrollment; Estrogen Receptors; Excision; Exposure to; FDA approved; Flagellin; Goals; Grant; Human; Immunity; Immunosuppression; Immunotherapy; Knowledge; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modality; Modeling; Mus; Myelogenous; Myeloid-derived suppressor cells; Neoadjuvant Therapy; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Primary Neoplasm; Progesterone Receptors; Publishing; Regimen; Rodent; Role; Safety; Salmonella; Septic Shock; Signal Pathway; Signal Transduction; Syndrome; T-Lymphocyte; TLR5 gene; Testing; Therapeutic; Toll-like receptors; Translating; Treatment Efficacy; Treatment-related toxicity; Tumor Immunity; Unresectable; Work; anti-PD-L1; anti-PD-L1 antibodies; base; breast cancer diagnosis; cancer type; chemotherapy; clinically relevant; combinatorial; effective therapy; human disease; immune checkpoint blockade; improved; in vivo; innovation; malignant breast neoplasm; melanoma; mouse model; neutrophil; nonhuman primate; novel; pre-clinical; programmed cell death ligand 1; response; survival outcome; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer diagnoses, is the most aggressive form of the disease, and has the poorest clinical outcome. Chemotherapy is the mainstay treatment for these patients despite significant treatment-related toxicities and short-term clinical responses. Therefore, the need for more effective and better tolerated treatment modalities for TNBC is warranted. Immune checkpoint blockade (ICB) is an immunotherapy-based approach that can reinvigorate durable immunity in advanced cancers such as melanoma and lung. In the case of other cancer types, such as breast cancer, the FDA approved the first immunotherapy for TNBC in March 2019. This regimen consists of α-PD-L1 antibody (Tecentriq) plus Abraxane (Nab-paclitaxel) as a frontline therapy for patients with unresectable locally advanced or metastatic PD-L1+ TNBC. Unfortunately, overall response rates remain relatively low and survival outcomes are extended for only a few months due in large part to expansion of immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) that potently suppress antitumor immunity. Thus, developing strategies to reduce PMN-MDSC activity may improve response rates to α-PD-L1/Abraxane in TNBC. One approach to lessen myeloid-based mechanisms of immune suppression is by modulating signaling pathways that govern immune suppression to those that promote stimulation in a concept known as reprogramming. Toll-like receptor (TLR) 5 signaling can both mitigate MDSC activity and stimulate antitumor immunity against multiple pre-clinical tumor models, including PD-L1+ TNBC. Thus, we posit that TLR5 agonists are a novel class of agents that can mediate myeloid reprogramming with potential in vivo therapeutic efficacy in PD-L1+ TNBC. To this end, we engineered and pharmacologically optimized entolimod, a derivative of the natural TLR5 agonist Salmonella flagellin. Importantly, three Phase I safety trials cumulatively involving nearly 200 subjects showed that systemically administered entolimod is safe. Our recent work showed that entolimod suppresses metastatic PD-L1+ TNBC by stimulating durable CD8+ T cell immunity. Here, we show that entolimod-driven PMN-MDSC reprogramming governs the anti-metastatic activity of entolimod in PD-L1+ TNBC. These findings provided the rationale for our additional studies showing that combining entolimod with α-PD-L1/Paclitaxel triggers regression of early-stage mouse PD-L1+ TNBC and induces durable immunity. However, whether entolimod enhances the antitumor activity of α-PD-L1/Abraxane in locally advanced and the neoadjuvant and/or adjuvant setting of metastatic PD- L1+ TNBC, for which this therapy is FDA approved, remains unknown, as well as whether entolimod alters the PMN-MDSC response as part of its mechanism of action. To test our central hypothesis, we propose two aims: (1) to determine the most effective TNBC treatment platform and disease setting by which entolimod bolsters the efficacy of α-PD-L1/Abraxane; and (2) to elucidate the contribution of PMN-MDSCs to the mechanism by which entolimod promotes the antitumor efficacy of α-PD-L1/Abraxane in TNBC.

三阴性乳腺癌(TNBC)占所有乳腺癌诊断的15%-20%，是最多的 这种疾病是一种侵袭性的疾病，临床结果最差。化疗是主要的治疗方法 对于这些患者，尽管存在显著的治疗相关毒性和短期临床反应。因此， 有必要对TNBC采取更有效和更好的耐受性治疗方式。免疫检查点 阻断(ICB)是一种基于免疫疗法的方法，可以重振晚期患者的持久免疫。 黑色素瘤和肺癌等癌症。对于其他癌症类型，如乳腺癌，FDA批准了 2019年3月首次对TNBC进行免疫治疗。该方案由α-PD-L1抗体(泰克)加 亚伯拉沙星(NAB-紫杉醇)作为不能切除的局部晚期或转移性肿瘤的一线治疗 PD-L1+TNBC。不幸的是，总体应答率仍然相对较低，生存结果延长。 仅仅几个月，很大程度上是由于免疫抑制的中性粒细胞来源的扩大 能有效抑制抗肿瘤免疫的抑制细胞(PMN-MDSCs)。因此，制定战略以 降低PMN-MDSC活性可能提高对α-PD-L1/Abraxane的应答率。一种减少 以髓系为基础的免疫抑制机制是通过调节支配免疫的信号通路 抑制是指在一种称为重新编程的概念中促进刺激的那些。Toll样受体(TLR)5 信号转导既能降低MDSC活性，又能激发抗多种临床前肿瘤免疫 型号，包括PD-L1+TNBC。因此，我们假设TLR5激动剂是一类新型的介导剂。 髓系重编程对PD-L1+TNBC的体内潜在治疗效果。为此，我们设计了 以及药理优化的entolimod，它是天然TLR5激动剂沙门氏菌鞭毛蛋白的衍生物。 重要的是，累计涉及近200名受试者的三个I期安全性试验表明，系统地 注射恩托莫特是安全的。我们最近的工作表明，恩托洛特通过以下方式抑制转移的PD-L1+TNBC 刺激持久的CD8+T细胞免疫。在这里，我们证明了内模驱动的PMN-MDSC重新编程 控制恩托莫特在PD-L1+TNBC中的抗转移活性。这些发现为我们的 更多研究表明，恩托莫特与α-PD-L1/紫杉醇联合使用可触发早期癌症的消退 小鼠PD-L1+TNBC，诱导持久免疫。然而，恩托莫特是否增强了抗肿瘤作用 α-PD-L1/Abraxane在局部晚期和转移性PD新佐剂和/或佐剂环境中的活性 FDA批准了这种疗法用于L1+TNBC，目前尚不清楚，以及恩托洛莫是否改变了 PMN-MDSC反应作为其作用机制的一部分。为了验证我们的中心假设，我们提出了两个目标： (1)确定最有效的TNBC治疗平台和疾病背景 α-PD-L1/Abraxane的疗效；以及(2)通过以下方式阐明PMN-MDSCs在机制中的贡献 哪种恩托莫特可促进α-PD-L1/Abraxane对肿瘤的抑制作用。