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: 10226591
• 负责人: Pamela Rosato
• 金额: $ 26.78万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226591
• 关键词: Affect; Antiviral Response; Cells; Clinical; Development; Effectiveness; Foundations; Frequencies; Genetic Transcription; Herpesvirus 1; Human; Immune; Immune response; Immunity; Immunotherapy; Individual; Infection; Inflammatory Response; Institutes; Light; Location; Malignant Neoplasms; Measles virus; Mus; Oncolytic viruses; Patient Care; Patient-Focused Outcomes; Patients; Solid Neoplasm; T cell response; T memory cell; T-Lymphocyte; Techniques; Testing; Therapeutic; Treatment Efficacy; Treatment Protocols; Tumor Tissue; Vaccination; Vaccinia virus; Viral Antigens; Virus; Work; base; cell killing; design; experimental study; immune activation; improved outcome; melanoma; mouse model; neoplastic cell; novel; oncolytic virotherapy; therapy outcome; tumor

Oncolytic viruses (OV) are a promising class of cancer therapeutics that work by preferentially infecting and killing tumor cells. Many OVs are viruses to which individuals have pre-existing immunity, 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是通过疫苗接种的个人具有先前免疫力的病毒 或自然感染（例如HSV-1，麻疹和牛ac病毒），但这种免疫对治疗的影响 功效和患者预后尚不清楚。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，可能是这些记忆 T细胞在OV治疗过程中会遇到病毒抗原。鉴于此，迫切需要了解 溶瘤病毒特异性T细胞对OV疗法的影响。本提案中的目标是（i）确定 肿瘤中存在的常见基于OV病毒的T细胞的频率和（ii）确定 这些T细胞增强OV疗法的程度。该提案以特定于病毒的发现为基础 T细胞在各种小鼠和人类肿瘤中丰富，并且会引起有效的炎症 重新遇到特定病毒抗原的反应，导致小鼠的肿瘤清除。鉴于此， 该提案将检验中心假设，即现有的OV特异性T细胞存储器将增强溶瘤 通过促进免疫激活和肿瘤细胞杀伤来治疗病毒。该假设将通过 整合研究小鼠和人肿瘤中转录和细胞变化的技术 组织。 AIM 1将利用黑色素瘤的小鼠模型来确定溶瘤病毒特异性T细胞的影响 关于OV疗法的功效，并评估不同的治疗时间表如何增强它。 AIM 2意志 检查人黑色素瘤肿瘤中溶瘤病毒特异性T细胞，研究其频率和 功能。通过定义抗病毒T细胞对OV疗法的反应，我们将提供强大的科学 可以制定完善和重新设计OV疗法的新策略的框架。共同 这些实验将提高我们对实体瘤免疫组成的理解，并告知 溶瘤病毒疗法的领域。该建议将为针对竞争性R01的基础 理解1）患者OV治疗期间的免疫反应，2）OV特异性的预测潜力 T细胞丰度在治疗结果上，3）如何对OV疗法进行改进或重新设计以改进 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。