Impact of TNF on Oncolytic Virotherapy

项目摘要：溶瘤病毒疗法(OV)代表了一种治疗各种实体肿瘤的新方法，通过 诱导抗肿瘤免疫反应。虽然这种疗法在各种疾病中都非常有效 在临床前模型中，将这些成功转化为人类患者已被证明具有挑战性。最近是这样的 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果的机制。然而，真正的本质是 这些监管途径仍不清楚。 我们实验室之前已经开发出一种新型的溶瘤MYXV，它表达一种可溶性的PD1抑制剂和一种 IL12融合蛋白(vPD1/IL12)。然而，这种结构在治疗播散性疾病方面非常有效， ~50%的肿瘤模型至少部分无反应，病毒治疗与 与免疫相关的不良事件的发生。在我们的后续研究中，我们对调解 VPD1/IL12的疗效我们观察到，在治疗过程中，病毒诱导了高水平的肿瘤坏死因子。令人惊讶的是， 无论是基因消除还是基于抗体的阻断这种肿瘤坏死因子都会显著增加 治疗效果显著，毒性显著降低。据我们所知，没有其他研究 肿瘤坏死因子阻断对OV有积极影响，因此涉及的机制(S)也是如此 至于如何利用这一发现改善临床结果仍不清楚。因此，我们提出了 目前的提案包含三个具体目标，旨在通过以下方式在我们令人兴奋的初步数据基础上建立基础： 明确肿瘤坏死因子抑制卵巢癌疗效的机制，了解肿瘤坏死因子如何介导卵巢癌-- 诱导的毒性，以及确定临床适用的方法，在卵巢癌期间应用肿瘤坏死因子受体阻滞剂。这部作品 不仅将促进我们现有的vPD1/IL12病毒的临床应用，而且还将增进我们对 成功的OV涉及的基本机制。

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.