Impact of pre-existing T cell memory on oncolytic virus therapy

预先存在的 T 细胞记忆对溶瘤病毒治疗的影响

基本信息

批准号：
10271750
负责人：
Pamela Rosato
金额：
$ 26.24万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10271750
关键词：
Antiviral Response CD8-Positive T-Lymphocytes Cell physiology Cells Cellular biology Clinical Development Effectiveness Excision Face Foundations Frequencies Gene Expression Genetic Transcription Goals Herpesvirus 1 Human Immune Immune response Immunity Immunotherapy Individual Infection Inflammatory Response Institutes Knowledge Light Location Malignant Neoplasms Measles virus Modeling Mus Oncolytic viruses Patient Care Patient-Focused Outcomes Patients Population Simplexvirus Slice Solid Solid Neoplasm Specificity T cell response T memory cell T-Lymphocyte Techniques Testing Therapeutic Tissues Treatment Efficacy Treatment Protocols Tumor Tissue Vaccination Vaccinia Vaccinia virus Vertebral column Viral Antigens Virus Virus Replication Work base cell killing cytotoxic design efficacy outcomes experimental study human pathogen immune activation improved improved outcome melanoma mouse model neoplasm immunotherapy neoplastic cell novel oncolytic virotherapy recruit response therapy outcome tumor tumor microenvironment virology

项目摘要

Oncolytic viruses (OV) are a promising class of cancer therapeutics that work by preferentially infecting and killing tumor cells. Many OVs are viruses which individuals have pre-existing immunity to, through vaccination or natural infection (e.g. HSV-1, measles, and vaccinia virus), yet the impact of this immunity on therapeutic efficacy and patient outcome is unclear. Recent findings have revealed that virus-specific memory T cells populate tumors, often to high frequency. Because of their location within the tumor, it is likely these memory T cells will encounter viral antigen during OV therapy. In light of this, there is a critical need to understand the impact of oncolytic virus-specific T cells on OV therapy. The objectives in this proposal are to (i) determine the frequencies of T cells specific for common OV-based viruses present in tumors and (ii) determine the extent to which these T cells strengthen OV therapy. This proposal builds on the findings that virus-specific T cells are abundant in a wide range of mouse and human tumors and can elicit potent inflammatory responses upon re-encountering their specific viral antigen, resulting in tumor clearance in mice. Given this, this proposal will test the central hypothesis that pre-existing OV-specific T cell memory will enhance oncolytic virus therapy by promoting immune activation and tumor cell killing. This hypothesis will be tested by integrating techniques examining transcriptional and cellular changes in both mouse and human tumor tissue. Aim 1 will utilize mouse models of melanoma to determine the impact of oncolytic virus-specific T cells on the efficacy of OV therapy and assess how different treatment schedules may enhance this. Aim 2 will examine oncolytic virus-specific T cells in human melanoma tumors, investigating their frequency and function. By defining the response of antiviral T cells to OV therapy, we will provide a strong scientific framework whereby new strategies to refine and re-design OV therapies can be developed. Collectively, these experiments will advance our understanding of the immune composition of solid tumors and inform the field of oncolytic viral therapies. This proposal will provide a foundation for a competitive R01 aimed at understanding 1) immune responses during OV therapy in patients, 2) the predictive potential of OV-specific T cell abundance on therapeutic outcome, and 3) how OV therapies can be refined or re-designed to improve outcome. In all, the studies proposed here will have an impact on clinical patient care and drive the development of novel immunotherapies.

溶瘤病毒（OV）是一类很有前途的癌症治疗方法，它通过优先感染和杀死肿瘤细胞。许多 OV 是个体通过疫苗接种或疫苗接种预先存在免疫力的病毒。自然感染（例如 HSV-1、麻疹和牛痘病毒），但这种免疫力对治疗效果的影响且患者的结果尚不清楚。最近的研究结果表明，病毒特异性记忆 T 细胞聚集在肿瘤，往往出现频率较高。由于它们位于肿瘤内，这些记忆 T 细胞很可能会在 OV 治疗期间遇到病毒抗原。有鉴于此，迫切需要了解 OV 治疗中的溶瘤病毒特异性 T 细胞。该提案的目标是 (i) 确定频率 T 细胞对肿瘤中常见的基于 OV 的病毒具有特异性，并且 (ii) 确定这些病毒的程度 T 细胞增强 OV 疗法。该提议建立在以下发现的基础上：病毒特异性 T 细胞在广泛的小鼠和人类肿瘤，在再次遇到时可以引发强烈的炎症反应它们的特异性病毒抗原，导致小鼠肿瘤清除。鉴于此，这项提议将考验中央假设预先存在的 OV 特异性 T 细胞记忆将通过促进免疫来增强溶瘤病毒治疗激活和杀伤肿瘤细胞。该假设将通过整合检查转录的技术来检验以及小鼠和人类肿瘤组织中的细胞变化。目标 1 将利用黑色素瘤小鼠模型确定溶瘤病毒特异性 T 细胞对 OV 疗法疗效的影响，并评估不同的差异治疗计划可能会增强这一点。目标 2 将检查人类黑色素瘤中的溶瘤病毒特异性 T 细胞肿瘤，研究它们的频率和功能。通过定义抗病毒 T 细胞对 OV 疗法的反应，我们将提供一个强大的科学框架，通过该框架，可以改进和重新设计 OV 疗法的新策略得到开发。总的来说，这些实验将增进我们对免疫成分的理解实体瘤并为溶瘤病毒疗法领域提供信息。该提案将为竞争性 R01 旨在了解 1) OV 治疗期间患者的免疫反应，2) 预测 OV 特异性 T 细胞丰度对治疗结果的潜力，以及 3) 如何改进 OV 疗法或重新设计以改善结果。总之，这里提出的研究将对临床患者护理产生影响并推动新型免疫疗法的发展。