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: 10908106
• 负责人: Dmitriy Zamarin
• 金额: $ 56.51万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908106
• 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.

项目概要/摘要 溶瘤病毒 (OV) 是一类新兴疗法，利用其在癌症中优先复制的能力 使用新城疫病毒 (NDV) 作为 OV 模型，我们是其中之一。 第一批鉴定 OV 诱导肿瘤浸润淋巴细胞并与免疫检查点协同作用的能力 基于这个原理，我们进行了腹膜内（IP）ONCOS-102（溶瘤药）的临床试验。 腺病毒）与抗 PD-L1 抗体 durvalumab 联合治疗晚期卵巢癌和 尽管有这些研究，但我们对 OV 如何相互作用的理解仍存在重大差距。 而 TIL 的增加或“使肿瘤变热”通常被用作反应的读数。 对于 OV 来说，这样的读数是高度非特异性的：(1) 目前尚不清楚 TIL 的增加是否主要代表 肿瘤反应性或OV反应性T细胞；（2）尚不清楚OV反应性T细胞是否有积极影响或消极影响 (3) 肿瘤反应性或OV反应性T细胞之间的平衡如何受到影响尚不清楚 在我们的初步研究中，我们发现瘤内 NDV 显着增加了 OV 的数量。 不同肿瘤部位之间共享的 T 细胞克隆以及治疗和远处的显性 T 细胞克隆 肿瘤与不同的 T 细胞表型相关，因此可能识别肿瘤反应性 T 细胞与 OV 反应性 T 细胞。 免疫学和遗传工具，例如 T 细胞受体 (TCR) 测序和单细胞 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，我们研究的主要目标是定义 OV 反应性 T 细胞和肿瘤反应性 T 细胞之间的平衡，以响应 OV 治疗和 确定 OV 反应性 T 细胞对 T 细胞介导的抗肿瘤免疫的影响 在目标 1 中，我们将确定 OV 反应性 T 细胞对 T 细胞介导的抗肿瘤免疫的影响。 与 OV 反应性和肿瘤反应性 T 细胞相关的不同 TCR 序列和表型，并将量化其 我们将确定先前的抗 OV 免疫和 OV 特异性 CD4 或 CD8 的平衡。 T 细胞影响抗肿瘤 T 细胞反应和治疗效果。为了确保我们的研究结果具有广泛的适用性，我们。 将在两种不同的小鼠模型中检验我们的假设：侧腹 B16 黑色素瘤和卵巢癌腹膜模型 MPB1 并将采用 NDV（RNA 病毒）和牛痘（DNA 病毒）作为两种生物学上不同的病毒模型。 将利用肿瘤微环境数据以及治疗前和治疗中肿瘤的 TCR 数据以及来自 我们对溶瘤腺病毒 ONCOS-102 与 durvalumab 联合进行的临床试验，以确定推定的 OV- 肿瘤反应性 T 细胞在肿瘤和外周血中进化，以及这些参数是否可以预测 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。 并使我们能够在“热与冷”的背景下了解 OV 诱导的 T 细胞反应的本质 这些发现对于了解试验中对 OV 的免疫反应的本质至关重要。 并促进未来制定旨在增强抗肿瘤而非抗OV免疫的策略。