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对其具有预先存在的免疫力的病毒 或自然感染(如HSV-1、麻疹和牛痘病毒)，但这种免疫对治疗的影响 疗效和患者结果尚不清楚。最近的研究发现，病毒特异性记忆T细胞 肿瘤广泛存在，通常频率很高。由于它们在肿瘤内的位置，很可能是这些记忆 T细胞在OV治疗过程中会遇到病毒抗原。有鉴于此，迫切需要了解 溶瘤病毒特异性T细胞对卵巢癌治疗的影响。本提案的目标是：(一)确定 肿瘤中存在的常见OV病毒特异性T细胞的频率和(Ii)决定 这些T细胞在多大程度上加强了卵巢癌的治疗。这项建议建立在病毒特异性研究结果的基础上 T细胞广泛存在于小鼠和人类的肿瘤中，并可引起强烈的炎性反应。 当再次遇到它们的特定病毒抗原时会产生反应，导致小鼠体内的肿瘤清除。鉴于此， 这一提议将检验一个中心假设，即预先存在的OV特异性T细胞记忆将增强溶瘤作用 通过促进免疫激活和肿瘤细胞杀伤来进行病毒治疗。这一假设将通过以下方式检验 检测小鼠和人类肿瘤转录和细胞变化的综合技术 组织。Aim 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治疗的有效性，并评估不同的治疗计划如何增强这一点。目标2将 检测人黑色素瘤中溶瘤病毒特异性T细胞，调查其频率和 功能。通过确定抗病毒T细胞对卵子疗法的反应，我们将提供强有力的科学依据 可据此制定改进和重新设计OV疗法的新战略的框架。总而言之， 这些实验将促进我们对实体肿瘤免疫成分的理解，并告知 溶瘤病毒治疗领域。这项提议将为竞争性的R01奠定基础，旨在 了解1)OV治疗患者的免疫反应，2)OV特异性的预测潜力 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治疗以改进 结果。总而言之，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.