Oncolytic Immunotherapy of Malignant Glioma

该项目涉及一种新的策略，用于治疗复发性，治疗耐药的脑肿瘤， 溶瘤免疫疗法溶瘤脊髓灰质炎病毒重组体PVSRIPO正在进行I期临床试验 针对复发性胶质母细胞瘤（GBM）。我们观察到有希望的完全临床缓解， 在一些先前手术、化疗、放疗失败的患者中，放射学反应，在某些情况下， 贝伐单抗治疗。值得注意的是，单次约6.5小时的瘤内病毒输注发生了持久的反应 副作用极小（均与PVSRIPO无关）。PVSRIPO是减毒活脊髓灰质炎病毒 1型（Sabin）疫苗，含有外源鼻病毒2型内部核糖体进入位点（IRES）。PVSRIPO是 由于正常CNS中限制性蛋白质合成控制所施加的限制，导致“神经元不胜任”。 脑内输注高达最大可行剂量的PVSRIPO证实了人类的神经毒性。 在灵长类动物毒理学研究中建立的减毒表型。然而，PVSRIPO在恶性细胞中茁壮成长 异位表达脊髓灰质炎受体，癌-胎儿细胞粘附分子Necl 5/CD 155。这是由于 这是一个组成型活性MAPK信号网络，有利于病毒翻译起始的非正统机制。 PVSRIPO感染GBM细胞具有强烈的细胞溶解作用， 动物肿瘤模型的反应。肿瘤细胞的致死性PVSRIP 0感染和非致死性转导/ 抗原呈递细胞的激活引起复杂的免疫反应，具有逆转免疫原性的潜力。 固有的免疫抑制性肿瘤微环境，并引发适应性抗肿瘤反应。这 该项目旨在研究临床脊髓灰质炎溶瘤病毒治疗的原理并解开宿主 对病毒性肿瘤感染的免疫反应。我们提出了三个目的：（1）PVSRIPO的临床研究 复发性GBM患者。我们将研究PVSRIPO病毒治疗的安全性，并监测临床 GBM患者中PVSRIPO溶瘤免疫治疗的免疫监测;（2）GBM患者中PVSRIPO溶瘤免疫治疗的免疫监测。 GBM患者。我们正在进行全面的免疫监测工作以解开宿主免疫- PVSRIPO溶瘤免疫治疗的机制;（3）阐明脊髓灰质炎病毒溶瘤免疫治疗的机制 转基因同基因小鼠胶质瘤模型中的病毒疗法。我们创造了一个新的，容易患脊髓灰质炎的， 允许在免疫活性细胞中研究PVSRIPO治疗机制的同基因肿瘤模型 hosts.

This project concerns a novel strategy for the treatment of recurrent, therapy-resistant brain tumors with oncolytic immunotherapy. The oncolytic poliovirus recombinant, PVSRIPO, is in ongoing Phase-I clinical trials against recurrent glioblastoma (GBM). We observed promising complete clinical remissions with near-complete radiographic responses in several patients that failed prior surgery, chemo-, radiation-, and -in some cases- bevacizumab therapy. Remarkably, durable responses occurred with a single, ~6.5h intratumoral virus infusion with minimal adverse effects (none of which related to PVSRIPO). PVSRIPO is the live-attenuated poliovirus type 1 (Sabin) vaccine containing a foreign, rhinovirus type-2 internal ribosomal entry site (IRES). PVSRIPO is 'neuron-incompetent', due to limits imposed by restrictive protein synthesis control in the normal CNS. Intracerebral infusion of up to the maximal feasible dose of PVSRIPO in humans confirmed the neuro- attenuated phenotype established in primate toxicology studies. Yet, PVSRIPO thrives in malignant cells ectopically expressing the polio receptor, the onco-fetal cell adhesion molecule Necl5/CD155. This is due to constitutively active MAPK signaling networks that favor an unorthodox mechanism of viral translation initiation. PVSRIPO infection of GBM cells has drastic cytolytic effects that produce sustained pro-inflammatory responses in animal tumor models. Lethal PVSRIPO infection of tumor cells and non-lethal transduction/ activation of antigen-presenting cells evokes complex immunologic reactions with the potential to reverse the inherently immune-suppressive tumor microenvironment and to elicit adaptive anti-tumor responses. This project is designed to investigate the principle of polio oncolytic virotherapy in the clinic and to unravel host immune responses to viral tumor infection. We propose three Aims: (1) Clinical investigation of PVSRIPO in patients with recurrent GBM. We will investigate the safety of PVSRIPO virotherapy and monitor the clinical and radiographic response in GBM patients; (2) Immune monitoring of PVSRIPO oncolytic immunotherapy in GBM patients. We are conducting a comprehensive immune monitoring effort to unravel host immune- mediated mechanisms of PVSRIPO oncolytic immunotherapy; (3) Elucidate mechanisms of poliovirus oncolytic virotherapy in a transgenic syngeneic mouse glioma model. We generated a novel, polio-susceptible, syngeneic tumor model that permits mechanistic investigations of PVSRIPO therapy in immune-competent hosts.