POTENTIATION OF ANTI-TUMOR IMMUNITY BY ONCOLYTIC VIRUS IN SITU VACCINATION

溶瘤病毒原位疫苗接种增强抗肿瘤免疫力

• 批准号: 10584115
• 负责人: Dmitriy Zamarin
• 金额: $ 7.93万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584115
• 关键词: Adenoviruses; Adoptive Transfer; Animal Model; Antigen-Presenting Cells; Bilateral; Blood; CD8-Positive T-Lymphocytes; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chemosensitization; Clinical; Clinical Trials; Clinical Trials Design; Clone Cells; Colorectal Cancer; Computational Biology; DNA; DNA Viruses; Data; Development; Distant; Engineering; Ensure; Equilibrium; Exhibits; Future; Genetic; Genetic Engineering; Human; Immune response; Immune system; Immunity; Immunologics; Immunology; Immunotherapy; Investments; Knowledge; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Microscopy; Modeling; Mus; Nature; Newcastle disease virus; Oncogenic Viruses; Oncolytic; Oncolytic viruses; Outcome; Ovarian Carcinoma; Patients; Peripheral; Peritoneal; Phenotype; Primary Neoplasm; RNA; RNA Viruses; Simplexvirus; Site; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Therapeutic; Treatment Efficacy; Tumor Expansion; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Vaccinia; Viral; Viral Antigens; Virus; adaptive immune response; anti-PD-L1 antibodies; anti-tumor immune response; antiviral immunity; cancer cell; clinical predictors; congenic; immune checkpoint blockade; in situ vaccination; intraperitoneal; melanoma; mouse model; neoplastic cell; oncolytic adenovirus; oncolytic virotherapy; peripheral blood; pre-clinical; response; single-cell RNA sequencing; synergism; tool; transcriptome sequencing; tumor; tumor microenvironment; virology

PROJECT SUMMARY/ABSTRACT Oncolytic viruses (OV) are an emerging class of therapeutics capitalizing on their preferential ability to replicate in cancer cells and modify the tumor microenvironment. Using Newcastle Disease Virus (NDV) as an OV model, we were one of the first groups to identify OV ability to induce tumor-infiltrating lymphocytes and synergize with immune checkpoint blockade. Based on this rationale, we have conducted a clinical trial of intraperitoneal (IP) ONCOS-102 (oncolytic adenovirus) in combination with anti-PD-L1 antibody durvalumab in patients with advanced ovarian and colorectal cancer (NCT02963831). Despite these studies, major gaps exist in our understanding of how OVs interact with the immune system. While an increase in TILs or “making tumors hot” is commonly used as a readout of response to OV, such readouts are highly nonspecific: (1) It is largely unknown whether the increase in TILs represents primarily tumor-reactive or OV-reactive T cells; (2) It is unknown whether the OV-reactive T cells positively or negatively impact anti-tumor immunity; (3) It is unknown how the balance between the tumor-reactive or OV-reactive T cells is influenced by biologically distinct OVs. In our preliminary studies, we find that intratumoral NDV markedly expands the number of T cell clones that are shared between the different tumor sites and that dominant T cell clones in the treated and distant tumors are associated with distinct T cell phenotypes, thus possibly identifying tumor- vs. OV-reactive T cells. Using immunologic and genetic tools such as T cell receptor (TCR) sequencing and single cell RNA-sequencing and our team’s expertise in computational biology, immunology and virology, the key objectives of our study are to define the balance between the OV-reactive and tumor-reactive T cells generated in response to OV therapy and to determine the impact of OV-reactive T cells on T cell-mediated anti-tumor immunity. In Aim 1, we will identify the distinct TCR sequences and phenotypes associated with OV-reactive and tumor-reactive T cells and will quantify their balance in the treated and distant tumors. We will determine how prior anti-OV immunity and OV-specific CD4 or CD8 T cells impact the anti-tumor T cell response and therapeutic efficacy. To ensure broad applicability of our findings, we will test our hypothesis in two distinct mouse models: flank B16 melanoma and peritoneal model of ovarian carcinoma MPB1 and will employ NDV (RNA virus) and vaccinia (DNA virus) as two biologically distinct virus models. In Aim 2, we will leverage the tumor microenvironment data as well as TCR data from pre- and on-treatment tumors and blood from our clinical trial of oncolytic adenovirus ONCOS-102 in combination with durvalumab to determine how putative OV- and tumor-reactive T cells evolve in tumors and in peripheral blood and whether these parameters are predictive of clinical benefit. This study will determine how different OVs activate anti-viral and anti-tumor adaptive immune response and will enable us to understand the nature of OV-induced T cell responses beyond “hot vs. cold” within the context of mouse and human studies. These findings will be key to understand the nature of immune responses to OVs in trials and to enable future development of strategies aiming to enhance anti-tumor rather than anti-OV immunity.

项目摘要/摘要 溶瘤病毒（OV）是一类新兴的治疗药，对其在癌症中复制的首选能力产生了影响 细胞并修改肿瘤微环境。使用纽卡斯尔病毒（NDV）作为OV模型，我们是之一 鉴定OV影响肿瘤浸润淋巴细胞并与免疫检查点协同作用的第一批组 glocade。基于此基本原理，我们进行了腹膜内（IP）Oncos-102的临床试验（Oncolytic 腺病毒）与晚期卵巢和晚期患者的抗PD-L1抗体Durvalumab结合 结直肠癌（NCT02963831）。尽管进行了这些研究，但我们对OV如何相互作用的理解仍然存在重大差距 使用免疫系统。虽然tils或“使肿瘤变热”的增加通常用作响应的读数 对于OV而言，此类读数高度非特异性：（1）在很大程度上不知道TIL的增加是否代表主要 肿瘤反应性或OV反应性T细胞； （2）尚不清楚OV反应性T细胞是积极还是负面影响 抗肿瘤免疫； （3）尚不清楚肿瘤反应性或OV反应T细胞之间的平衡如何受到影响 通过生物学上不同的OV。在我们的初步研究中，我们发现肿瘤内NDV明显扩大了数量 T细胞克隆在不同的肿瘤部位之间共享的T细胞克隆以及所处理和远处的主要T细胞克隆 肿瘤与不同的T细胞表型有关，因此可能鉴定出肿瘤与OV反应性T细胞。使用 免疫学和遗传工具，例如T细胞受体（TCR）测序以及单细胞RNA - 测序以及我们的 团队在计算生物学，免疫学和病毒学方面的专业知识，我们研究的关键目标是定义 OV反应性和肿瘤反应性T细胞在响应OV疗法以及对 确定OV反应T细胞对T细胞介导的抗肿瘤免疫的影响。在AIM 1中，我们将确定 与OV反应性和肿瘤反应性T细胞相关的独特的TCR序列和表型，并将量化其 在治疗和远处的肿瘤中保持平衡。我们将确定先前的抗VOV免疫和OV特异性CD4或CD8如何 T细胞会影响抗肿瘤T细胞反应和治疗效率。为了确保我们的发现的广泛适用性，我们 将在两个不同的小鼠模型中检验我们的假设：侧面B16黑色素瘤和卵巢癌腹膜模型 MPB1并将采用NDV（RNA病毒）和牛vicinia（DNA病毒）作为两个生物学上不同的病毒模型。在AIM 2中，我们 将利用肿瘤微环境数据以及来自治疗前和治疗肿瘤的TCR数据以及来自 我们对溶瘤腺病毒ONCOS-102与Durvalumab结合的临床试验，以确定推定的OV- 肿瘤反应性T细胞在肿瘤和周围血液中演变，以及这些参数是否可以预测 临床益处。这项研究将确定不同的OV如何激活抗病毒和抗肿瘤适应性免疫反应 并将使我们能够在“热与冷”之外了解OV诱导的T细胞响应的性质 小鼠和人类研究。这些发现将是了解试验中免疫反应的性质的关键 并实现未来的战略制定旨​​在增强抗肿瘤而不是抗VOV免疫力。