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

基本信息

  • 批准号:
    9815079
  • 负责人:
  • 金额:
    $ 10.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目摘要/摘要。 非小细胞肺癌和肝细胞癌是癌症死亡的主要原因 全球范围内。免疫检查点抑制物(CPIs),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 包括非小细胞肺癌和肝细胞癌。尽管有如此广泛的活动范围,只有不到50%的患者接受了 从这些化合物中持续受益。此外,大多数取得应答的患者将 一年内复发。临床上对克服耐药性的治疗方法的需求尚未得到满足。 提高CPI疗法的疗效。药效学监测已纳入临床试验 为了确定CPI治疗耐药的机制,表明免疫浸润水平低的肿瘤, 或“冷”肿瘤,往往对检查点抑制反应较差。溶瘤病毒疗法使用工程病毒 杀灭肿瘤细胞,促进抗肿瘤免疫。已经对几种溶瘤病毒疗法进行了评估 临床上,最近批准了一种溶瘤疱疹病毒(T-VEC)用于治疗晚期黑色素瘤。Vyriad是 开发水疱性口炎病毒(VSV),一种有效的溶瘤病毒治疗平台,作为静脉治疗 治疗晚期癌症。Vsv-干扰素β-nis,一种工程化的重组vsv,已显示出强大的临床前 目前正在对晚期癌症患者进行静脉治疗的临床试验中测试。 临床前研究表明,VSV选择性地放大和杀死肿瘤细胞,导致快速和 小鼠肿瘤模型单次静脉注射治疗后持久的肿瘤缓解。静脉VSV 治疗还可引起肿瘤内CD8+T细胞的浸润。PD-1/PD-L1阻滞剂的加入延长了持续时间 在小鼠结直肠肿瘤模型中,T细胞的渗透显著增强肿瘤的缓解。这些数据 表明溶瘤的破坏促进了T细胞的涌入,而局部免疫抑制信号可以 被检查点抑制剂阻断,以促进抗肿瘤T细胞反应的激活和放大。 这些协同作用有可能克服对单抗的初级和获得性抗性。 代理检查点抑制疗法。我们的目标是在临床上推进联合溶瘤病毒- 免疫治疗途径治疗CPI难治性非小细胞肺癌和肝细胞癌这一目标在 这项SBIR快速通道建议将Vyriad在溶瘤病毒治疗开发方面的专业知识与 梅奥诊所早期癌症治疗计划的世界级专业知识。拟议的临床研究将 提供关键的可行性和有效性信号,并指明支持快速推进这一目标的行动模式 联合溶瘤病毒免疫疗法治疗CPI难治性癌

项目成果

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ALEX A. ADJEI其他文献

ALEX A. ADJEI的其他文献

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{{ truncateString('ALEX A. ADJEI', 18)}}的其他基金

Phase 2 Clinical Trials Program for Experimental Therapeutics Clinical Trials Network
实验疗法临床试验网络二期临床试验计划
  • 批准号:
    9094959
  • 财政年份:
    2014
  • 资助金额:
    $ 10.8万
  • 项目类别:
Network Lead Academic Participating Site Grant from the Roswell Cancer Inst.
罗斯威尔癌症研究所的网络领导学术参与站点资助。
  • 批准号:
    8846079
  • 财政年份:
    2014
  • 资助金额:
    $ 10.8万
  • 项目类别:
NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis
NCI 实验治疗-临床试验网络,重点为 1 期
  • 批准号:
    9086290
  • 财政年份:
    2014
  • 资助金额:
    $ 10.8万
  • 项目类别:
Data & Safety Monitoring
数据
  • 批准号:
    7714444
  • 财政年份:
    2008
  • 资助金额:
    $ 10.8万
  • 项目类别:
Protocol-Specific Research Support
特定于协议的研究支持
  • 批准号:
    7714441
  • 财政年份:
    2008
  • 资助金额:
    $ 10.8万
  • 项目类别:
Protocol Review & Monitoring
方案审查
  • 批准号:
    7714440
  • 财政年份:
    2008
  • 资助金额:
    $ 10.8万
  • 项目类别:
Clinical Research Services
临床研究服务
  • 批准号:
    7714435
  • 财政年份:
    2008
  • 资助金额:
    $ 10.8万
  • 项目类别:
Protocol Review and Monitoring System
方案审查和监控系统
  • 批准号:
    7432964
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
Protocol Specific Research
协议特定研究
  • 批准号:
    7432966
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
Data and Safety Monitoring
数据和安全监控
  • 批准号:
    7432961
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
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