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: 10004595
• 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/10004595
• 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; Epithelium; 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; 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.

项目概要/摘要 PD-1/PD-L1免疫检查点的阻断促进了不同类型患者的治疗 然而，PD-1/PD-L1 阻断受到低反应率和有限持续时间的限制。 在某些情况下的反应，例如非小细胞肺癌 (NSCLC)、三阴性乳腺癌 (TNBC)，以及卵巢癌、前列腺癌和结直肠癌，这些发现至少部分是由以下因素解释的。 前提是 PD-1/PD-L1 轴只是众多肿瘤免疫抑制机制之一 需要抑制。 因此，显然需要额外的策略来改善人类癌症的免疫治疗。 在这方面，癌细胞会激活免疫逃避程序，例如诱导 PD-L1 促进先天性和适应性免疫反应的效应子的表达和下调。 迄今为止，此类免疫抑制计划的发现和靶向取得的成功有限，支持 迫切需要确定激活这些程序的信号通路。 MUC1-C 癌蛋白在人类癌症中异常过度表达，并且与不良预后相关 MUC1-C 促进上皮间质转化 (EMT) 和癌症干细胞。 (CSC) 状态。最近的进展表明 MUC1-C 还可以激活免疫逃避程序。 在人类癌细胞中，包括 PD-L1 表达上调和免疫抑制 此外，还发现靶向 MUC1-C 可以有效逆转肿瘤免疫。 逃避。 这些发现强调需要开发针对 MUC1-C 的药物 通过这种方式，可以产生针对 MUC1-C 的选择性且有效的抗体。 细胞外结构域正在开发为抗体-药物偶联物 (ADC) 和抗体- 此外，MUC1-C 细胞质的肽抑制剂。 基于该药物抑制 PD-L1 的发现，已在纳米颗粒制剂中开发了结构域 表达并激活免疫微环境中的抗肿瘤 T 细胞。 MUC1-C 靶向药物将在基因工程小鼠模型 (GEMM) 中进行研究 单独和联合使用时的抗肿瘤活性以及对免疫微环境的影响 这些研究将与 MUC1-C 表达的评估相结合。 人类肿瘤作为抑制性免疫微环境的指标。 靶向 MUC1-C 的药物已作为新型免疫治疗药物进入临床评估阶段。