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

溶瘤病毒（OV）是一类有希望的癌症治疗剂，其通过优先感染和感染肿瘤细胞来起作用。 杀死肿瘤细胞。许多OV是个体通过疫苗接种或免疫接种而具有预先存在的免疫力的病毒。 自然感染（如HSV-1、麻疹和牛痘病毒），但这种免疫力对治疗效果的影响 患者结局尚不清楚。最近的研究结果表明，病毒特异性记忆T细胞在 肿瘤，往往以高频率。由于它们在肿瘤内的位置，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 溶瘤病毒特异性T细胞对OV治疗的影响。本建议的目标是（i）确定频率 对肿瘤中常见的基于OV的病毒具有特异性的T细胞的数量，以及（ii）确定这些 T细胞加强OV治疗。这一提议建立在以下发现的基础上：病毒特异性T细胞在一个细胞中是丰富的。 广泛的小鼠和人类肿瘤，并可在再次遇到时引发有效的炎症反应 它们的特异性病毒抗原，导致小鼠的肿瘤清除。鉴于此，这一提议将考验中央政府 假设预先存在OV特异性T细胞记忆将通过促进免疫增强溶瘤病毒治疗 激活和杀死肿瘤细胞。这一假设将通过整合技术检测转录 以及小鼠和人类肿瘤组织中的细胞变化。Aim 1将利用小鼠黑色素瘤模型， 确定溶瘤病毒特异性T细胞对OV治疗功效的影响，并评估 治疗方案可能会增强这一点。目的2将检测人黑色素瘤中溶瘤病毒特异性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治疗的反应， 我们将提供一个强有力的科学框架，使改进和重新设计OV疗法的新策略能够 发展。总的来说，这些实验将促进我们对免疫组成的理解。 实体瘤的研究，并为溶瘤病毒疗法领域提供信息。这一建议将为一项 竞争性R 01旨在了解1）患者OV治疗期间的免疫应答，2） OV特异性T细胞丰度对治疗结果的潜在影响，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病人护理产生影响 并推动新型免疫疗法的发展。

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.