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