Investigating mechanisms of peptide alarm therapy

研究肽警报疗法的机制

基本信息

批准号：
10066658
负责人：
Noah Veis Gavil
金额：
$ 4.08万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066658
关键词：
Adaptive Immune System Agonist Alleles Antibodies Antigens Antitumor Response Antiviral Agents Automobile Driving Binding Biological Assay Blood CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology CTLA4 gene Cancer cell line Cell Line Cell physiology Cells Cellular biology Cessation of life Clinical Cytomegalovirus Data Doctor of Philosophy Engineering Environment Exercise Exhibits Goals Histocompatibility Antigens Class I Human Human Herpesvirus 4 Immune Immune system Immunologic Surveillance Immunologics Immunology Immunotherapy Inflammatory Influenza Injections Interferons Internal Medicine Laboratories Licensing Location MHC Class I Genes Measures Mediating Medical Melanoma Cell Memory Mentorship Metastatic Melanoma Minnesota Modeling Monitor Mus Natural Killer Cells Normal tissue morphology Oral mucous membrane structure Patients Peptide/MHC Complex Peptides Peripheral Physicians Positioning Attribute Primary Infection Process Production Recording of previous events Resistance Role Scientist Sentinel Skin Solid Neoplasm Specialist Specificity Structure of parenchyma of lung Surveillance Program System T memory cell T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte Testing Therapeutic Uses Tissues Training Training Programs Translational Research Transplantation Treatment Efficacy Tumor Antigens Tumor Immunity Tumor-Infiltrating Lymphocytes Universities Variant Viral Virus Virus Diseases Work anti-PD-L1 anti-tumor immune response arm cancer cell cancer immunotherapy cancer therapy career cell type chemokine curative treatments cytokine cytotoxic flu immune activation immune checkpoint blockade melanoma mouse model neoplasm immunotherapy neoplastic cell novel novel strategies novel therapeutics pathogen pathogenic virus pre-clinical pre-doctoral programmed cell death protein 1 programs protein complex recruit response success synergism tumor tumor growth tumor-immune system interactions

项目摘要

Project Summary/Abstract: Cancer Immunotherapies shift tumor microenvironments from immunosuppressive to immune-activated. Despite some success with potentially-curative treatments, many patients do not exhibit durable responses, necessitating novel approaches to enhance tumor immunotherapy. “Peptide alarm therapy” is a novel cancer immunotherapy that repurposes antiviral memory CD8+ T cells within tumors to drive antitumor immunity. After a primary infection, pathogen-specific CD8+ T cells establish a surveillance program that positions T cells throughout the entire body. In particular, resident-memory CD8+ T cells (Trm) permanently reside in all tissues after primary antigen exposure. In addition to normal tissue, antiviral Trm populate solid tumors. Notably, in contrast to tumor-specific T cells, intratumoral antiviral Trm are not exhausted and demonstrate potent immune activation upon engagement with their cognate antigen. Our group showed that Trm reactivation in both normal tissues and tumors leads to inflammatory processes, including the production of immune-stimulatory cytokines and chemokines (e.g. IFNg, TNFa, CCL9), and the local recruitment of effector molecules (e.g. antibodies) and immune cells (e.g. circulating memory T cells, NK cells). The intratumoral injection of peptide, and this subsequent reactivation of antiviral Trm, induces tumor growth suppression and exhibits synergy with immune checkpoint blockade, specifically aPD-L1. The mechanisms driving this antitumor immune response remain uncharacterized. In this proposal, I will employ well-established murine models of T cell memory and melanoma to explore the mechanisms that drive the antitumor response of peptide alarm therapy. Aim 1 will determine whether viral peptide presentation by cancer cells is necessary for treatment efficacy, potentially demonstrating that, through peptide alarm therapy, antiviral Trm can directly kill cancer cells in a peptide:MHCI-dependent mechanism. Aim 2 will measure and monitor tumor-specific T cells and NK cells, determining their respective role in controlling tumor growth in the context of this cancer therapy. Not only will this work add value to preclinical data for a promising new immunotherapy, but it will also relay information about how Trm can be manipulated for therapeutic use. This proposal will be completed at the University of Minnesota in the laboratory of David Masopust, Ph.D., a world-leader in the study of memory T cell function and immunosurveillance. Along with mentorship from Dr. Masopust, the collaborative training environment at the University’s Center for Immunology and the integrated training provided by the Medical Scientist Training Program (dual-degree MD/PhD program) will serve as an ideal location for me to develop as a predoctoral trainee. My long-term career goal is to become an academic physician scientist who drives translational research as an internal medicine clinician and specialist in immunology.

项目摘要/摘要：癌症免疫疗法将肿瘤微环境从免疫抑制转移到免疫激活。尽管在潜在术治疗方面有一些成功，但许多患者不存在耐用的反应，但需要采取新颖的方法来增强肿瘤免疫疗法。 “肽警报疗法”是一种新型癌症免疫疗法可以重新利用肿瘤内抗病毒记忆CD8+ T细胞以驱动抗肿瘤免疫力。原发性感染后，病原体特异性的CD8+ T细胞建立了一个监测程序，该程序将T细胞定位在整个身体中。特别是，居民记忆CD8+ T细胞（TRM）永久驻留在所有组织中初级抗原暴露后。除正常组织外，抗病毒TRM还填充了实体瘤。值得注意的是，与肿瘤特异性T细胞相反，肿瘤内抗病毒TRM并未耗尽并证明与它们的同源抗原互动后，有效的免疫激活。我们的小组表明TRM 正常组织和肿瘤的重新激活导致炎症过程，包括免疫刺激细胞因子和趋化因子（例如IFNG，TNFA，CCL9）和局部的产生效应分子（例如抗体）和免疫细胞（例如循环记忆T细胞，NK细胞）的募集。胡椒的肿瘤内注射以及随后的抗病毒TRM的重新激活，诱导肿瘤生长抑制和与免疫障碍物封锁的协同作用，特别是APD-L1。驱动这种抗肿瘤免疫增强响应的机制仍然没有表征。在这个建议中，我将雇用建立的T细胞记忆和黑色素瘤的鼠模型探索驱动的机制肽警报疗法的抗肿瘤反应。 AIM 1将确定病毒肽是否通过癌细胞对于治疗效率是必要的，有可能证明，通过肽警报疗法，抗病毒TRM可以直接杀死肽中的癌细胞：MHCI依赖性机制。 AIM 2将测量和监测肿瘤特异性T细胞和NK细胞，确定它们在控制肿瘤生长中的作用这种癌症疗法的背景。这项工作不仅会为临床前数据增加价值免疫疗法，但还将传达有关如何操纵TRM以供治疗使用的信息。该提案将在明尼苏达大学的大卫·马萨普斯特（David Masopust）博士实验室完成。在记忆T细胞功能和免疫监视的研究中，世界领导者。以及Dr. Masopust，大学免疫学中心的合作培训环境和综合的医学科学家培训计划（双学位医学博士/博士学位计划）提供的培训将作为我可以发展为一名志愿学员的理想位置。我的长期职业目标是成为一个学术物理科学家将转化研究作为内科临床和免疫学专家。