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.

项目摘要/摘要 溶瘤病毒(OV)是一类新兴的治疗药物，利用其在癌症中优先复制的能力 细胞，改变肿瘤微环境。使用新城疫病毒(NDV)作为OV模型，我们是 首批确定卵巢蛋白诱导肿瘤浸润性淋巴细胞并与免疫检查点协同作用的小组 封锁。基于这一理论，我们进行了一项腹膜内注射ONCOS-102(溶瘤)的临床试验 联合抗PD-L1抗体治疗晚期卵巢癌和卵巢癌 结直肠癌(NCT02963831)。尽管有这些研究，但在我们对虚拟现实如何互动的理解上仍存在很大差距 与免疫系统有关。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)TILs的增加是否主要代表了 肿瘤反应性T细胞或卵巢反应性T细胞；(2)卵巢反应性T细胞对肿瘤或卵巢反应性T细胞的积极或负面影响尚不清楚 抗肿瘤免疫；(3)肿瘤反应性或卵巢反应性T细胞之间的平衡如何受到影响尚不清楚 通过生物学上不同的OV。在我们的初步研究中，我们发现肿瘤内的新城疫病毒显著扩大了 在不同肿瘤部位之间共享的T细胞克隆，以及在治疗和远程治疗中的主要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细胞与卵巢反应性T细胞。vbl.使用 免疫和遗传工具，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 卵巢反应性T细胞与肿瘤反应性T细胞之间的平衡 确定卵巢反应性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 与卵子反应性和肿瘤反应性T细胞相关的不同TCR序列和表型，并将量化它们的 治疗后的肿瘤和远处肿瘤之间的平衡。我们将确定先前的抗OV免疫和OV特异性的CD4或CD8 T细胞影响T细胞的抗肿瘤反应和治疗效果。为了确保我们的研究结果具有广泛的适用性，我们 将在两个不同的小鼠模型中验证我们的假设：侧翼B16黑色素瘤和卵巢癌腹膜模型 MPB1，并将使用新城疫病毒(RNA病毒)和牛痘病毒(DNA病毒)作为两个生物学上不同的病毒模型。在目标2中，我们 将利用肿瘤微环境数据以及来自治疗前和治疗中的肿瘤和血液的TCR数据 我们对溶瘤腺病毒ONCOS-102联合Durvalumab的临床试验，以确定推测的OV- 肿瘤反应性T细胞在肿瘤和外周血中的进化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 并将使我们能够理解OV诱导的T细胞反应的本质，而不是在以下背景下的“热与冷” 老鼠和人类的研究。这些发现将是在试验中理解OVS免疫反应性质的关键 并使未来能够开发旨在增强抗肿瘤免疫而不是抗OV免疫的策略。