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）是一类很有前途的癌症治疗药物，它通过优先感染和抑制肿瘤细胞而起作用