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

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 杀死肿瘤细胞。许多OV是个人通过接种疫苗或接种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)，但这种免疫对治疗效果的影响 而患者的结果也不清楚。最近的发现表明，病毒特异的记忆T细胞 肿瘤，通常是高频率的。由于它们在肿瘤内的位置，这些记忆T细胞很可能会 在卵巢癌治疗过程中遇到病毒抗原。有鉴于此，迫切需要了解 OV治疗中的溶瘤病毒特异性T细胞。这项建议的目标是：(一)确定频率 肿瘤中存在的常见OV病毒的特异性T细胞和(Ii)确定这些 T细胞强化OV治疗。这一建议建立在病毒特异性T细胞丰富的研究结果的基础上。 小鼠和人的肿瘤范围广泛，复发时可引发强烈的炎症反应 它们的特定病毒抗原，导致肿瘤在小鼠体内清除。鉴于此，这项提议将考验中央银行 假设预先存在的卵巢特异性T细胞记忆将通过促进免疫来加强溶瘤病毒的治疗 激活和杀伤肿瘤细胞。这一假说将通过整合技术来检验转录 以及小鼠和人类肿瘤组织中的细胞变化。Aim 1将利用黑色素瘤的小鼠模型 确定溶瘤病毒特异性T细胞对卵巢癌治疗效果的影响，并评估不同 治疗计划可能会加强这一点。AIM 2将检测人类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细胞对卵子疗法的反应， 我们将提供一个强大的科学框架，使改进和重新设计OV疗法的新战略能够 被开发出来。总的来说，这些实验将促进我们对人类免疫系统的免疫成分的理解。 实体肿瘤，并为溶瘤病毒治疗领域提供信息。这项提议将为 竞争性R01旨在了解1)OV治疗期间患者的免疫反应，2)预测 卵巢特异性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.