Clinical evaluation of combination oncolytic viro-immunotherapy for solid tumors

溶瘤病毒免疫联合疗法治疗实体瘤的临床评价

• 批准号: 9815079
• 负责人: ALEX A. ADJEI
• 金额: $ 10.8万
• 依托单位: VYRIAD, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815079
• 关键词: Address; Advanced Malignant Neoplasm; Biological; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Etiology; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Colorectal Neoplasms; Combined Modality Therapy; Correlative Study; Data; Development; Disease Progression; Disease remission; Dose; Engineering; Failure; Goals; Herpesviridae; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppressive Agents; Immunotherapy; Infiltration; Intravenous; Malignant Neoplasms; Measurable; Measures; Mediating; Modeling; Monitor; Mus; Non-Small-Cell Lung Carcinoma; Oncolytic; Outcome; PD-1/PD-L1; Patients; Pharmacodynamics; Phase; Primary carcinoma of the liver cells; Quality of life; Radiology Specialty; Recombinants; Refractory; Relapse; Resistance; Running; SLEB2 gene; Safety; Signal Transduction; Small Business Innovation Research Grant; Solid Neoplasm; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tumor Burden; Tumor Escape; Tumor Immunity; Tumor-infiltrating immune cells; Vesicular stomatitis Indiana virus; Viremia; Virus; Virus Inhibitors; advanced disease; checkpoint inhibition; checkpoint therapy; clinical efficacy; effective therapy; immune checkpoint blockade; immunotherapeutic virotherapy; improved; melanoma; neoplastic cell; oncolytic Vesicular Stomatitis Virus; oncolytic virotherapy; pharmacokinetics and pharmacodynamics; phase 2 study; preclinical efficacy; preclinical study; programs; research clinical testing; resistance mechanism; response; safety and feasibility; therapy outcome; treatment response; tumor

PROJECT SUMMARY/ABSTRACT . Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are leading cause of cancer death globally. Immune checkpoint inhibitors (CPIs), which block tumor immune-evasion signals and activate T-cell mediated antitumor immunity, have demonstrated clinical efficacy and are approved for several cancers including NSCLC and HCC. Despite this broad spectrum of activity, less than 50% of patients receive any sustained benefit from these compounds. Moreover the majority of patients who achieve a response will relapse within a year. There is an unmet clinical need for therapeutic approaches that overcome resistance and enhance efficacy of CPI therapies. Pharmacodynamics monitoring has been incorporated into clinical trials to define mechanisms of resistance to CPI therapy, indicating that tumors with low levels of immune infiltration, or `cold' tumors, tend to respond poorly to checkpoint inhibition. Oncolytic virotherapy uses engineered viruses to destroy tumor cells and promote antitumor immunity. Several oncolytic virotherapies have been evaluated clinically with the recent approval of an oncolytic Herpesvirus (T-VEC) to treat advanced melanoma. Vyriad is developing Vesicular stomatitis virus (VSV), a potent oncolytic virotherapy platform, as an intravenous therapy for advanced cancer. VSV-IFNβ-NIS, an engineered recombinant VSV, has demonstrated potent preclinical efficacy and is currently being tested in a clinical trial for intravenous therapy of patients with advanced cancer. Preclinical studies demonstrate that VSV selectively amplifies in and kills tumor cells resulting in rapid and durable tumor remission following single-shot intravenous therapy in murine tumor models. Intravenous VSV therapy also elicits intratumoral CD8+ T-cell infiltration. The addition of PD-1/PD-L1 blockade extends duration of T-cell infiltration to significantly enhance tumor remission in a murine colorectal tumor model. These data indicate that oncolytic tumor destruction promotes influx of T-cells, while local immunosuppressive signals can be blocked by checkpoint inhibitors to promote activation and amplification of antitumor T-cell responses. These synergistic interactions have the potential to overcome both primary and acquired resistance to single- agent checkpoint inhibitor therapy. Our goal is to clinically advance the combination oncolytic viro- immunotherapy approach to treat patients with CPI refractory NSCLC and HCC. This goal is addressed in this SBIR Fast-track proposal by combining Vyriad's expertise in oncolytic virotherapy development with the world-class expertise of the Mayo Clinic Early Cancer Therapeutics Program. The proposed clinical study will provide critical feasibility and efficacy signals and indicate mode of action to support rapid advancement of this combination oncolytic viro-immunotherapy approach to treat CPI refractory cancer.

项目总结/摘要。 非小细胞肺癌（NSCLC）和肝细胞癌（HCC）是癌症死亡的主要原因 在全球免疫检查点抑制剂（CPI）阻断肿瘤免疫逃避信号并激活T细胞 介导的抗肿瘤免疫，已证明临床疗效，并被批准用于几种癌症 包括NSCLC和HCC。尽管有这种广泛的活性，但只有不到50%的患者接受任何治疗。 从这些化合物中获益。此外，大多数获得缓解的患者将 一年内复发。对于克服耐药性的治疗方法存在未满足的临床需求 并增强CPI疗法的功效。药效学监测已纳入临床试验 以确定对CPI治疗的抗性机制，表明具有低水平免疫浸润的肿瘤， 或“冷”肿瘤倾向于对检查点抑制反应差。溶瘤病毒疗法使用工程病毒 破坏肿瘤细胞，促进抗肿瘤免疫。已经对几种溶瘤病毒疗法进行了评价 临床上最近批准了溶瘤疱疹病毒（T-VEC）治疗晚期黑素瘤。维耶利斯 开发水泡性口炎病毒（VSV），一种有效的溶瘤病毒治疗平台，作为静脉内治疗 治疗晚期癌症VSV-IFNβ-NIS是一种工程化的重组VSV， 疗效，目前正在临床试验中进行测试，用于晚期癌症患者的静脉治疗。 临床前研究表明，VSV选择性地扩增并杀死肿瘤细胞，导致快速和 在鼠肿瘤模型中单次注射静脉内治疗后的持久肿瘤缓解。静脉内VSV 治疗还增加了肿瘤内CD 8 + T细胞浸润。添加PD-1/PD-L1阻断剂可延长持续时间 的T细胞浸润，以显著增强小鼠结肠直肠肿瘤模型中的肿瘤缓解。这些数据 表明溶瘤性肿瘤破坏促进T细胞流入，而局部免疫抑制信号可 被检查点抑制剂阻断，以促进抗肿瘤T细胞应答的激活和扩增。 这些协同相互作用有可能克服对单克隆抗体的原发性和获得性抗性。 检查点抑制剂治疗。我们的目标是在临床上推进溶瘤病毒- 免疫治疗方法治疗CPI难治性NSCLC和HCC患者。这一目标在 这SBIR快速通道的建议相结合，Vyellow在溶瘤病毒疗法的发展与 马约诊所早期癌症治疗项目的世界级专业知识。拟议的临床研究将 提供关键的可行性和有效性信号，并指出支持快速推进这一进程的行动模式 本发明提供了一种组合溶瘤病毒免疫治疗方法以治疗CPI难治性癌症。