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 疾病的侵略性形式，并且具有最差的临床结局。化学疗法是主要治疗 对于这些患者，尽管有严重的治疗相关战术和短期临床反应。所以， 有必要需要更有效，更好的TNBC治疗方式。免疫检查点 goolocade（ICB）是一种基于免疫疗法的方法，可以在晚期中恢复耐用的免疫组织化学 黑色素瘤和肺等癌症。对于其他癌症类型，例如乳腺癌，FDA批准了 TNBC于2019年3月进行的第一种免疫疗法。该方案由α-PD-L1抗体（Tecentriq）Plus组成 Abraxane（Nab-Paclitaxel）作为无法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，总体响应率相对较低，生存结果延长 仅几个月就由于免疫抑制性多形核髓样衍生的大部分时间 抑制细胞（PMN-MDSC）可能抑制抗肿瘤免疫。那，制定策略来 降低PMN-MDSC活性可以提高TNBC中对α-PD-L1/Abraxane的反应率。一种减少的方法 基于髓样免疫抑制的机制是通过调节控制免疫的信号通路 抑制那些在称为重编程概念中促进刺激的人。 Toll样受体（TLR）5 信号传导既可以减轻MDSC活性，又可以刺激抗肿瘤的免疫组织术对多个临床前肿瘤 模型，包括PD-L1+ TNBC。那就是我们海报，TLR5激动剂是一种可以调节的新型代理类 髓样重编程，具有PD-L1+ TNBC中潜在的体内治疗效率。为此，我们设计了 和药物优化的Enlimod，天然TLR5激动剂沙门氏菌鞭毛蛋白的衍生物。 重要的是，三阶段安全试验累计涉及近200名受试者 管理的Enlimod是安全的。我们最近的工作表明，Enlimod通过 刺激耐用的CD8+ T细胞免疫。在这里，我们证明了ENLIMOD驱动的PMN-MDSC重新编程 控制Entolimod在PD-L1+ TNBC中的抗转移活性。这些发现为我们提供了理由 其他研究表明，将Enlimod与α-PD-L1/紫杉醇触发的早期回归相结合 小鼠PD-L1+ TNBC并影响耐用的免疫力。但是，Entolimod是否增强了抗杀菌剂 α-PD-L1/Abraxane在局部晚期和新辅助和/或调整转移性PD-的活性 该疗法获得FDA批准的L1+ TNBC仍然未知，以及Enlimod是否改变了 PMN-MDSC响应是其作用机理的一部分。为了检验我们的中心假设，我们提出了两个目标： （1）确定Entolimod Bolsters的最有效的TNBC治疗平台和疾病设置 α-PD-L1/abraxane的效率； （2）通过 这促进了TNBC中α-PD-L1/abraxane的抗肿瘤效率。