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

基本信息

  • 批准号:
    10224740
  • 负责人:
  • 金额:
    $ 82.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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DONALD W. KUFE其他文献

DONALD W. KUFE的其他文献

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{{ truncateString('DONALD W. KUFE', 18)}}的其他基金

Targeting MUC1-C with an antibody drug conjugate for the therapy of advanced prostate cancer
使用抗体药物偶联物靶向 MUC1-C 治疗晚期前列腺癌
  • 批准号:
    10512804
  • 财政年份:
    2022
  • 资助金额:
    $ 82.97万
  • 项目类别:
Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression
靶向 MUC1-C 治疗小细胞肺癌进展
  • 批准号:
    10354347
  • 财政年份:
    2022
  • 资助金额:
    $ 82.97万
  • 项目类别:
Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression
靶向 MUC1-C 治疗小细胞肺癌进展
  • 批准号:
    10563188
  • 财政年份:
    2022
  • 资助金额:
    $ 82.97万
  • 项目类别:
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:
    9789217
  • 财政年份:
    2018
  • 资助金额:
    $ 82.97万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 82.97万
  • 项目类别:
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:
    10478059
  • 财政年份:
    2018
  • 资助金额:
    $ 82.97万
  • 项目类别:
MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏
  • 批准号:
    9913473
  • 财政年份:
    2012
  • 资助金额:
    $ 82.97万
  • 项目类别:
MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏
  • 批准号:
    9238148
  • 财政年份:
    2012
  • 资助金额:
    $ 82.97万
  • 项目类别:
Functional role of the MUC1-C oncoprotein in non-small cell lung cancer
MUC1-C 癌蛋白在非小细胞肺癌中的功能作用
  • 批准号:
    8837576
  • 财政年份:
    2012
  • 资助金额:
    $ 82.97万
  • 项目类别:
Functional role of the MUC1-C oncoprotein in non-small cell lung cancer
MUC1-C 癌蛋白在非小细胞肺癌中的功能作用
  • 批准号:
    8634063
  • 财政年份:
    2012
  • 资助金额:
    $ 82.97万
  • 项目类别:

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