Repurposing TRM for tumor immunotherapy

重新利用 TRM 进行肿瘤免疫治疗

• 批准号: 10064999
• 负责人: DAVID MASOPUST
• 金额: $ 55.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-04 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064999
• 关键词: Abscopal effect; Adaptive Immune System; Address; Adjuvant; Anatomy; Antibodies; Antigen Presentation; Antiviral Agents; Cancer Model; Cell physiology; Cells; Clinical; Clinical Treatment; Clinical Trials; Common Neoplasm; Data; Distant; Environment; Evaluation; Future; Goals; Human; Immune; Immunity; Immunotherapeutic agent; Immunotherapy; Investigation; Malignant Neoplasms; Measurable; Modeling; Mus; Natural Killer Cells; Patients; Peptides; Phenotype; Preparation; Primary Neoplasm; Recrudescences; Recurrence; Role; Site; Solid Neoplasm; Surveys; T cell response; T memory cell; T-Lymphocyte; Testing; Tissues; Tumor Biology; Viral; Virus; Virus Diseases; anti-PD-L1; anti-cancer; antiviral immunity; arm; cancer immunotherapy; cytokine; experience; fighting; immune checkpoint blockade; immunogenic; in vivo; melanoma; neoantigens; neoplasm immunotherapy; novel strategies; prevent; programmed cell death ligand 1; recruit; response; sound; synergism; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Abstract: Repurposing TRM for tumor immunotherapy Overcoming the immunosuppressive tumor microenvironment and localizing adoptive cell and checkpoint blockade therapies to solid tumors remain major impediments to successful cancer immunotherapy. This proposal addresses these issues. Preliminary data indicates that human tumors are populated with antiviral T cells that remain competent to trigger immunostimulatory sensing and alarm function upon local recognition of cognate peptide. In mice, peptide alarm therapy synergizes with PD-L1 to clear tumors and mice are durably protected against tumor growth at alternative anatomic sites in the absence of further treatment. This proposal will dissect the mechanisms by which peptide alarm therapy triggers tumor clearance and establishes systemic tumor-specific immunity. It will test synergy with other immunotherapies. Further investigations will be made on the ability to recapitulate peptide alarm therapy on human tumor explants in anticipation of informing a clinical trial. This proposal may have a sustained impact on the field by defining a new avenue of cancer immunotherapy that operates independently but synergizes with other therapies.

摘要：重新定位TRM用于肿瘤免疫治疗 克服免疫抑制的肿瘤微环境，定位过继细胞和检查点 实体瘤的阻断治疗仍然是癌症免疫治疗成功的主要障碍。这 提案解决了这些问题。初步数据表明，人类肿瘤中充满了抗病毒T细胞 局部识别后仍有能力触发免疫刺激传感和警报功能的细胞 同源肽。在小鼠中，多肽警报疗法与PD-L1协同清除肿瘤，小鼠是持久的 在没有进一步治疗的情况下，防止肿瘤在其他解剖部位生长。这项建议 将剖析多肽警报疗法触发肿瘤清除并建立系统的机制 肿瘤特异性免疫。它将测试与其他免疫疗法的协同作用。警方会就以下事项作进一步调查 对人类肿瘤植入物进行多肽警报治疗的能力 审判。这一提议可能会通过定义一条癌症免疫治疗的新途径，对该领域产生持续的影响 这是独立运作的，但与其他疗法协同作用。