Investigating mechanisms of peptide alarm therapy

研究肽警报疗法的机制

基本信息

批准号：
10643974
负责人：
Noah Veis Gavil
金额：
$ 4.3万
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/10643974
关键词：
Adaptive Immune System Agonist Alleles Antibodies Antigens Antitumor Response Automobile Driving Binding Blood CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cancer cell line Cell Line Cell physiology Cells Cellular biology Cessation of life 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 clinical translation curative treatments cytokine cytotoxic detection assay flu immune activation immune checkpoint blockade influenza infection melanoma mouse model neoplasm immunotherapy neoplastic cell novel novel strategies novel therapeutics pathogen pathogenic virus pre-clinical pre-doctoral 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变为免疫激活。尽管潜在治愈性治疗取得了一些成功，但许多患者并未表现出持久的反应， “肽警报疗法”是一种新型癌症免疫疗法重新利用肿瘤内的抗病毒记忆 CD8+ T 细胞来驱动抗肿瘤免疫。初次感染后，病原体特异性 CD8+ T 细胞建立一个监视程序，对 T 细胞进行定位特别是，常驻记忆 CD8+ T 细胞 (Trm) 永久驻留在所有组织中。在暴露于原发性抗原后，除了正常组织外，抗病毒 Trm 也会出现在实体瘤中。值得注意的是，与肿瘤特异性 T 细胞相比，肿瘤内抗病毒 Trms 并未耗尽，并且证明我们的研究小组表明，Trm 与同源抗原结合后会产生有效的免疫激活。正常组织和肿瘤的重新激活会导致炎症过程，包括免疫刺激细胞因子和趋化因子（例如 IFNg、TNFa、CCL9）的产生以及局部效应分子（例如抗体）和免疫细胞（例如循环记忆 T 细胞、NK 细胞）的募集。瘤内注射肽，以及随后抗病毒 Trm 的重新激活，诱导肿瘤生长抑制并与免疫检查点阻断（特别是 aPD-L1）表现出协同作用。在本提案中，我将采用驱动这种抗肿瘤免疫反应的机制。完善的 T 细胞记忆和黑色素瘤小鼠模型，以探索驱动 T 细胞记忆和黑色素瘤的机制肽警报疗法的抗肿瘤反应将决定病毒肽是否呈递。癌细胞对于治疗效果是必要的，这可能表明，通过肽警报疗法，抗病毒 Trm 可以通过肽：MHCI 依赖性机制直接杀死癌细胞。监测肿瘤特异性 T 细胞和 NK 细胞，确定它们各自在控制肿瘤生长中的作用这项工作不仅会为有希望的新疗法的临床前数据增加价值。免疫疗法，但它也会传递有关如何操纵 Trm 进行治疗的信息。该提案将在明尼苏达大学 David Masopust 博士的实验室中完成，记忆 T 细胞功能和免疫监视研究领域的世界领先者，并得到了 Dr. 的指导。 Masopust，大学免疫学中心的协作培训环境和综合医学科学家培训计划（双学位MD/PhD计划）提供的培训将作为这是我作为博士前实习生发展的理想场所我的长期职业目标是成为一名博士生。作为内科临床医生推动转化研究的学术医师科学家免疫学专家。