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

• 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
• 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

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）是一类有希望的癌症治疗剂，通过优先感染和 杀死肿瘤细胞。许多OV是个体可以通过疫苗接种或 自然感染（例如HSV-1，麻疹和离甲酸病毒），但这种免疫力对治疗功效的影响 患者的结果尚不清楚。最近的发现表明病毒特异性记忆T细胞填充 肿瘤，通常是高频。由于它们在肿瘤中的位置，这些记忆T细胞很可能会 OV治疗期间会遇到病毒抗原。鉴于此，迫切需要了解 OV疗法上的溶瘤病毒特异性T细胞。该提案中的目标是（i）确定频率 针对肿瘤中存在的常见基于OV的病毒的T细胞和（ii）确定这些细胞的程度 T细胞增强OV疗法。该提案建立在一个发现中，病毒特异性T细胞在A中很丰富 各种各样的小鼠和人类肿瘤，可以在重新发生时引起有效的炎症反应 它们的特异性病毒抗原，导致小鼠肿瘤清除。鉴于此，该建议将测试中央 假设先前存在的OV特异性T细胞记忆将通过促进免疫来增强溶瘤病毒疗法 激活和肿瘤细胞杀死。该假设将通过集成研究转录的技术来检验 小鼠和人类肿瘤组织的细胞变化。 AIM 1将利用黑色素瘤的小鼠模型 确定溶瘤病毒特异性T细胞对OV治疗功效的影响，并评估如何不同 治疗时间表可能会增强这一点。 AIM 2将检查人黑色素瘤中的溶瘤病毒特异性T细胞 肿瘤，研究其频率和功能。通过定义抗病毒T细胞对OV治疗的反应， 我们将提供一个强大的科学框架，从而使用新的策略来完善和重新设计OV疗法可以 被开发。总的来说，这些实验将促进我们对免疫组成的理解 实体瘤并告知溶瘤病毒疗法的领域。该建议将为 旨在理解的竞争性R01 1）患者OV治疗期间的免疫反应，2）预测 OV特异性T细胞在治疗结果上的潜力，以及3）如何完善OV疗法或 重新设计以改善结果。总之，此处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。