MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies

MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点

• 批准号: 10224740
• 负责人: DONALD W. KUFE
• 金额: $ 82.97万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224740
• 关键词: Address; Advanced Development; Antibodies; Antibody-drug conjugates; Antitumor Response; Automobile Driving; Bispecific Antibodies; Breast Cancer Cell; CCL2 gene; Cancer Patient; Carcinoma; Clinical; Colorectal; Colorectal Cancer; Cytoplasmic Tail; Development; Disease; Down-Regulation; Epigenetic Process; Epithelial; Extracellular Domain; Formulation; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Homodimerization; Human; Immune; Immune Evasion; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammatory; Interferon Type II; Interferons; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mesenchymal; Mismatch Repair; Monoclonal Antibodies; Mucin 1 protein; Natural Immunity; Non-Small-Cell Lung Carcinoma; Oncogenic; Oncoproteins; Outcome; Ovarian; PD-1 blockade; PD-1/PD-L1; PD-L1 blockade; PDL1 inhibitors; Pathogenesis; Pathway interactions; Patients; Peptides; Progression-Free Survivals; Prostate; Research; Role; Signal Pathway; Solid Neoplasm; Surface; Survival Rate; T-Lymphocyte; Therapeutic; Tumor Escape; Tumorigenicity; Up-Regulation; adaptive immune response; adaptive immunity; antibody-dependent cell cytotoxicity; base; cancer cell; cancer immunotherapy; cancer stem cell; cancer type; checkpoint inhibition; clinical candidate; immune checkpoint; immune resistance; improved; inhibitor/antagonist; nanoparticle; novel; overexpression; pembrolizumab; programmed cell death ligand 1; programs; research clinical testing; response; self-renewal; stem-like cell; success; targeted agent; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Blockade of the PD-1/PD-L1 immune checkpoint has advanced the treatment of patients with diverse types of solid tumors. However, PD-1/PD-L1 blockade has been limited by low response rates and limited durations of response in certain settings, such as non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), as well as ovarian, prostate and colorectal cancers. These findings are explained, at least in part, by the premise that the PD-1/PD-L1 axis is only one of a number of tumor immune suppressive mechanisms that require inhibition. Therefore, additional strategies are clearly needed to improve the immunotherapy of human cancers. In this respect, cancer cells activate a program of immune evasion involving, for example, induction of PD-L1 expression and the downregulation of effectors that promote innate and adaptive immune response. The discovery and targeting of such immune suppressive programs has had limited success to date, supporting a critical need for identifying signaling pathways that activate these programs. The MUC1-C oncoprotein is aberrantly overexpressed in human carcinomas and is associated with poor clinical outcomes. MUC1-C promotes the epithelial-mesenchymal transition (EMT) and the cancer stem cell (CSC) state. Recent advances have demonstrated that MUC1-C also activates a program of immune evasion in human cancer cells that includes upregulation of PD-L1 expression and the suppression of immune effectors, such as IFN. In addition, targeting MUC1-C has been found to effectively reverse tumor immune evasion. These findings have emphasized the need for developing agents that target MUC1-C for the immunotherapy of human cancers. In this way, selective and potent antibodies generated against the MUC1-C extracellular domain are under development as an antibody-drug conjugate (ADC) and for antibody- dependent cell-mediated cytotoxicity (ADCC). In addition, a peptide inhibitor of the MUC1-C cytoplasmic domain has been developed in a nanoparticle formulation, based on the findings that this agent inhibits PD-L1 expression and activates anti-tumor T cells in the immune microenvironment. The MUC1-C-targeted agents will be studied in genetically-engineered mouse models (GEMMs) for anti-tumor activity, as well as effects on the immune microenvironment when used alone and in combination with PD-1/PD-L1 axis blockade. These studies will be integrated with assessment of MUC1-C expression in human tumors as a metric of the suppressive immune microenvironment. The overall goal will be to develop agents that target MUC1-C and are advanced to clinical evaluation as novel immunotherapeutics.

项目摘要/摘要 PD-1/PD-L1免疫座位的封锁已推进了不同类型患者的治疗 实体瘤。但是，PD-1/PD-L1封锁受到低响应率和持续时间有限的限制 在某些情况下的反应，例如非小细胞肺癌（NSCLC），三重阴性乳腺癌 （TNBC）以及卵巢，前列腺和结直肠癌。这些发现至少部分通过 PD-1/PD-L1轴只是许多肿瘤免疫抑制机制之一的前提 需要抑制。 因此，显然需要其他策略来改善人类癌症的免疫疗法。在 这方面，癌细胞激活了一个免疫进化程序，涉及PD-L1的诱导 促进先天和适应性免疫响应的作用的表达和下调。这 迄今 识别激活这些程序的信号通路的批判性需求。 MUC1-C癌蛋白在人癌中异常过表达，并且与较差有关 临床结果。 MUC1-C促进上皮 - 间质转变（EMT）和癌症干细胞 （CSC）状态。最近的进步表明，MUC1-C还激活了免疫进化程序 在人类癌细胞中，包括上调PD-L1表达和免疫的抑制 效应子，例如IFN。另外，已经发现靶向MUC1-C有效地反向肿瘤免疫 逃避。 这些发现强调需要开发靶向MUC1-C的剂 人类癌症的免疫疗法。这样，对MUC1-C产生的选择性和潜在抗体 细胞外结构域正在发展为抗体 - 药物缀合物（ADC），用于抗体 - 依赖性细胞介导的细胞毒性（ADCC）。另外，MUC1-C细胞质的肽抑制剂 基于该药物抑制PD-L1的发现，域已在纳米颗粒公式中开发 在免疫微环境中表达并激活抗肿瘤T细胞。 MUC1-C靶向剂将在基因工程的小鼠模型（GEMMS）中研究 抗肿瘤活性以及单独使用时对免疫微环境的影响 带有PD-1/PD-L1轴阻滞。这些研究将与评估MUC1-C表达的评估 人类肿瘤作为抑制性免疫微环境的度量。总体目标是发展 靶向MUC1-C并将其作为新型免疫治疗药的临床评估的药物。