Repurposing TRM for tumor immunotherapy

重新利用 TRM 进行肿瘤免疫治疗

• 批准号: 10549817
• 负责人: DAVID MASOPUST
• 金额: $ 48.04万
• 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/10549817
• 关键词: Abscopal effect; Adaptive Immune System; Address; Adjuvant; Anatomy; Antibodies; Antigen Presentation; Cancer Model; Cell physiology; Cells; Clinical; Clinical Treatment; Clinical Trials; Common Neoplasm; Data; Distant; Environment; Evaluation; Future; Goals; Human; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Infection; Innate Immune System; Investigation; Malignant Neoplasms; Measurable; Modeling; Mus; Natural Killer Cells; Patients; Peptides; Phenotype; Preparation; Primary Neoplasm; Productivity; 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; memory retention; neoantigens; neoplasm immunotherapy; novel strategies; prevent; programmed cell death ligand 1; recruit; response; sound; synergism; tissue resident memory T cell; 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：重新利用 TRM 进行肿瘤免疫治疗 克服免疫抑制肿瘤微环境并定位过继细胞和检查点 对实体瘤的封锁疗法仍然是成功的癌症免疫疗法的主要障碍。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 细胞在局部识别后仍能触发免疫刺激传感和警报功能 同源肽。在小鼠中，肽警报疗法与 PD-L1 协同作用以清除肿瘤，并且小鼠持久地 在没有进一步治疗的情况下，可以防止其他解剖部位的肿瘤生长。这个提议 将剖析肽警报疗法触发肿瘤清除并建立系统性机制 肿瘤特异性免疫。它将测试与其他免疫疗法的协同作用。将进一步调查 能够对人类肿瘤外植体进行肽警报治疗，以期为临床提供信息 审判。该提案可能通过定义癌症免疫治疗的新途径对该领域产生持续影响 它独立运作，但与其他疗法协同作用。