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是个体通过接种疫苗而具有预先存在的免疫力的病毒 或自然感染（例如HSV-1、麻疹和牛痘病毒），但这种免疫对治疗的影响 疗效和患者结局尚不清楚。最近的研究结果表明，病毒特异性记忆T细胞 肿瘤，通常是高频率的。因为它们位于肿瘤内，所以这些记忆 在OV治疗期间，T细胞将遇到病毒抗原。有鉴于此，我们迫切需要了解 溶瘤病毒特异性T细胞对OV治疗的影响。本提案的目标是：（一）确定 对肿瘤中存在的常见的基于OV的病毒特异性的T细胞的频率，以及（ii）确定 这些T细胞加强OV治疗的程度。这项建议建立在病毒特异性 T细胞在广泛的小鼠和人类肿瘤中大量存在，并且可以引起强烈的炎症反应。 在重新遇到它们的特异性病毒抗原时产生应答，导致小鼠中的肿瘤清除。鉴于此， 这项提议将检验中心假设，即预先存在的OV特异性T细胞记忆将增强溶瘤性， 通过促进免疫激活和杀死肿瘤细胞来进行病毒治疗。这一假设将由以下人员进行检验： 检测小鼠和人类肿瘤中转录和细胞变化的集成技术 组织.目的1将利用小鼠黑色素瘤模型来确定溶瘤病毒特异性T细胞的影响 OV治疗的疗效，并评估不同的治疗方案如何提高这一点。目标2将 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， 功能通过定义抗病毒T细胞对OV治疗的反应，我们将提供强有力的科学依据。 这是一个新的框架，可以开发新的策略来改进和重新设计OV疗法。总的来说， 这些实验将促进我们对实体瘤免疫组成的理解， 溶瘤病毒疗法领域。本建议书将为竞争性R 01提供基础， 了解1）患者OV治疗期间的免疫反应，2）OV特异性抗体的预测潜力， T细胞丰度对治疗结果的影响，以及3）如何改进或重新设计OV疗法以改善 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 开发新的免疫疗法。

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.