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: 10463811
• 负责人: Scott I. Abrams
• 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: 2021-08-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463811
• 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%，是最常见的乳腺癌。 该疾病的侵袭性形式，临床结果最差。化疗是主要治疗方法 尽管存在显着的治疗相关毒性和短期临床反应，但对这些患者来说。所以， TNBC 需要更有效和更好耐受的治疗方式。免疫检查点 封锁（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力 癌症，如黑色素瘤和肺癌。对于其他癌症类型，例如乳腺癌，FDA 批准 2019年3月首次针对TNBC的免疫疗法。该方案由α-PD-L1抗体（Tecentriq）加上 Abraxane（白蛋白结合型紫杉醇）作为不可切除的局部晚期或转移性患者的一线治疗 PD-L1+ TNBC。不幸的是，总体缓解率仍然相对较低，生存结果延长 仅仅几个月，很大程度上是由于免疫抑制性多形核骨髓来源的扩张 有效抑制抗肿瘤免疫的抑制细胞（PMN-MDSC）。因此，制定战略 减少 PMN-MDSC 活性可能会提高 TNBC 中对 α-PD-L1/Abraxane 的反应率。一种减少的方法 基于骨髓的免疫抑制机制是通过调节控制免疫的信号通路 抑制那些促进刺激的概念，称为重编程。 Toll 样受体 (TLR) 5 信号传导既可以减轻 MDSC 活性，又可以刺激针对多种临床前肿瘤的抗肿瘤免疫 型号，包括 PD-L1+ TNBC。因此，我们假设 TLR5 激动剂是一类新型药物，可以介导 骨髓重编程对 PD-L1+ TNBC 具有潜在的体内治疗功效。为此，我们设计了 以及药理优化的恩托莫德，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 名受试者的三项 I 期安全性试验表明，系统性地 给予恩托莫德是安全的。我们最近的工作表明，entolimod 通过以下方式抑制转移性 PD-L1+ TNBC： 刺激持久的 CD8+ T 细胞免疫力。在这里，我们展示了 entolimod 驱动的 PMN-MDSC 重编程 控制恩托莫德在 PD-L1+ TNBC 中的抗转移活性。这些发现为我们的研究提供了理论依据 其他研究表明，恩托莫德与 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 并诱导持久免疫。然而，恩托莫德是否能增强抗肿瘤作用？ α-PD-L1/Abraxane 在局部晚期和转移性 PD-的新辅助和/或辅助环境中的活性 L1+ TNBC（该疗法已获得 FDA 批准）仍不清楚，以及恩托莫德是否会改变 PMN-MDSC 反应是其作用机制的一部分。为了检验我们的中心假设，我们提出两个目标： (1) 确定恩托莫德支持的最有效的 TNBC 治疗平台和疾病环境 α-PD-L1/Abraxane 的功效； (2)通过以下方式阐明PMN-MDSCs对该机制的贡献 其中entolimod可促进α-PD-L1/Abraxane在TNBC中的抗肿瘤功效。