Impact of TNF on Oncolytic Virotherapy

TNF 对溶瘤病毒治疗的影响

• 批准号: 10731525
• 负责人: Eric Carter Bartee
• 金额: $ 43.82万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731525
• 关键词: Address; Antibodies; Apoptosis; Binding; Cells; Chimeric Proteins; Clinical; Data; Development; Disease; Enzymes; FDA approved; Failure; Follow-Up Studies; Genetic; Goals; Human; Immune; Inflammation; Interferons; Interleukin-12; Knowledge; Mediating; Membrane; Methods; Modeling; Molecular; Myxoma virus; Nature; Oncolytic; Oncolytic viruses; Outcome; PD-1 inhibitors; PD-1/PD-L1; Pathway interactions; Patients; Play; Pre-Clinical Model; Property; Receptors, Tumor Necrosis Factor, Type II; Regulatory Pathway; Role; Solid Neoplasm; Specificity; T-Lymphocyte; TNF gene; TNFRSF1B gene; Testing; Therapeutic antibodies; Toxic effect; Translating; Translations; Treatment Efficacy; Tumor Immunity; Viral; Virus; Virus Replication; Work; anti-tumor immune response; cancer infiltrating T cells; clinical application; clinical effect; clinical translation; design; immune clearance; immune-related adverse events; improved; in vivo; inhibitor; novel; oncolytic virotherapy; prevent; success; synergism; tumor; tumor microenvironment

Project Summary: Oncolytic virotherapy (OV) represents a novel method to treat a variety of solid tumors by inducing anti-tumor immune responses. While this therapy has been extremely efficacious in a wide variety of preclinical models, translating these successes into human patients has proven challenging. It has recently become clear that one of the major reasons for these failures is the existence of immune-regulatory mechanisms which dampen the efficacy of virally induced anti-tumor immunity. However, the exact nature of these regulatory pathways remains unclear. Our lab has previously developed a novel oncolytic MYXV which expresses a soluble PD1 inhibitor and an IL12 fusion protein (vPD1/IL12). This construct is highly effective at treating disseminated disease, however, ~50% of tumor models remain at least partially non-responsive and viral treatment is associated with the development of immune-related adverse events. In our follow-up studies into the mechanisms mediating the efficacy of vPD1/IL12 we have observed that the virus induces high levels of TNF during therapy. Strikingly, both genetic elimination or antibody-based blockade of this TNF results in a significant INCREASE in therapeutic efficacy as well as a significant REDUCTION in toxicity. To our knowledge, no other studies have demonstrated a positive impact of TNF blockade on OV and therefore both the mechanism(s) involved as well as how to leverage this finding into improved clinical outcomes remains unclear. We therefore put forth the current proposal which contains three specific aims designed to build off of our exciting preliminary data by: identifying the mechanism through which TNF restricts OV efficacy, understanding how TNF mediates OV- induced toxicities, and determining clinically applicable methods to apply TNF-blockade during OV. This work will advance not only the clinical use of our existing vPD1/IL12 virus, but also improve our understanding of the basic mechanisms involved in successful OV.

项目概述：溶瘤病毒疗法（OV）是一种通过以下方式治疗各种实体瘤的新方法： 诱导抗肿瘤免疫应答。虽然这种疗法在各种各样的疾病中非常有效， 临床前模型，将这些成功转化为人类患者已被证明具有挑战性。它最近 很明显，这些失败的主要原因之一是免疫调节的存在。 抑制病毒诱导的抗肿瘤免疫效力的机制。然而， 这些调控途径仍不清楚。 我们的实验室先前已经开发了一种新的溶瘤MYXV，它表达可溶性PD 1抑制剂和一种抗肿瘤药物。 IL 12融合蛋白（vPD 1/IL 12）。然而，这种构建体在治疗播散性疾病方面非常有效， 约50%的肿瘤模型至少部分保持无反应，病毒治疗与肿瘤的发生有关。 发生免疫相关不良事件。在我们的后续研究中， vPD 1/IL 12的功效我们已经观察到病毒在治疗过程中诱导高水平的TNF。引人注目的是， 这种TNF的基因消除或基于抗体的阻断均导致 治疗效果以及毒性的显著降低。据我们所知，没有其他研究 证实了TNF阻断对OV的积极影响，因此这两种机制也都涉及 因为如何利用这一发现来改善临床结果仍不清楚。我曾为他们做过一件事。 目前的提案包含三个具体目标，旨在通过以下方式建立我们令人兴奋的初步数据： 确定TNF限制OV疗效的机制，了解TNF如何介导OV-1， 诱导的毒性，并确定在OV期间应用TNF阻断的临床适用方法。这项工作 不仅将推进我们现有的vPD 1/IL 12病毒的临床应用，还将提高我们对vPD 1/IL 12病毒的认识。 成功OV的基本机制。