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

项目总结/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 实体肿瘤的然而，PD-1/PD-L1阻滞剂受到低应答率和有限持续时间的限制 在某些情况下，如非小细胞肺癌（NSCLC）、三阴性乳腺癌 （TNBC），以及卵巢癌、前列腺癌和结肠直肠癌。这些发现至少部分可以解释为， PD-1/PD-L1轴只是许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疗法。在 在这方面，癌细胞激活免疫逃避程序，包括例如诱导PD-L1 表达和下调促进先天性和适应性免疫应答的效应物。的 迄今为止，这种免疫抑制程序的发现和靶向已经取得了有限的成功，这支持了 识别激活这些程序的信号通路的关键需求。 MUC 1-C癌蛋白在人类肿瘤中异常过表达， 临床结果。MUC 1-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，MUC 1-C也激活免疫逃避程序 在人类癌细胞中，包括PD-L1表达上调和免疫抑制， 效应物，如IFN γ。此外，已经发现靶向MUC 1-C可以有效逆转肿瘤免疫 逃避 这些发现强调了开发靶向MUC 1-C的药物的必要性， 人类癌症的免疫疗法。以这种方式，产生了针对MUC 1-C的选择性和有效的抗体， 细胞外结构域作为抗体-药物偶联物（ADC）和用于抗体-药物偶联物（ADC）正在开发中。 依赖性细胞介导的细胞毒性（ADCC）。此外，MUC 1-C细胞质的肽抑制剂 基于这种药物抑制PD-L1的发现， 表达并激活免疫微环境中的抗肿瘤T细胞。 将在基因工程小鼠模型（GEMM）中研究MUC 1-C靶向剂， 抗肿瘤活性，以及单独和联合使用时对免疫微环境的影响 PD-1/PD-L1轴阻滞。这些研究将与MUC 1-C表达的评估相结合， 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MUC 1-C并作为新型免疫治疗剂进入临床评估的试剂。

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.