Oncolytic Virotherapy for Multiple Myeloma using VSV

项目摘要-摘要 尽管治疗多发性骨髓瘤(MM)的新药物已经开发出来，但播散性血浆 细胞恶性肿瘤，这种疾病仍然无法治愈，在美国影响着大约65,000名患者，造成超过10,000人 每年的死亡人数。迫切需要新的、创新的疗法，这种疗法可以对 复发或难治性MM的患者在Mayo的一项临床试验中，最近发现溶瘤 病毒疗法可使多发性骨髓瘤患者缓解，首次成功使用单针疗法 全身溶瘤治疗临床毒性最小且短暂的播散性癌症。我们 建议在这一临床成功的基础上，利用一种新的溶瘤剂，水泡性口炎病毒(VSV)，以及 RNA病毒具有几个生物学特性，使其特别适合于治疗人类癌症：(I)它是一种快速的 复制的高免疫原性病毒，通过直接细胞溶解和强劲刺激介导肿瘤破坏 抗肿瘤免疫，(Ii)普通人群对VSV的原有免疫力低，(Iii)VSV增长到高 允许大规模临床级病毒生产的滴度&(Iv)VSV在人类中通常是非致病性的。 最后，骨髓瘤细胞在体外和骨髓瘤小鼠模型中尤其容易受到VSV溶瘤的影响。 VSV在癌症模型中显示出强大的溶瘤效果，促使一项合作努力 将这一前景看好的新疗法转化为临床。这导致了临床前毒理学的成功完成 研究、GMP病毒制造和评估瘤内Vsv-hIFNβ的I期临床试验的启动 肝细胞癌患者的治疗。我们开发了一种新型的重组VSV表达 静脉注射干扰素-β(干扰素β)和钠碘转运体(β-NIS)治疗慢性粒细胞白血病 播散性骨髓瘤。临床前研究表明，单次静脉注射vsv-h干扰素β-nis对慢性阻塞性肺疾病有疗效。 免疫功能良好的同基因骨髓瘤小鼠模型。小鼠干扰素β表达增强肿瘤选择性 并刺激抗肿瘤免疫力。NIS表达允许对病毒复制进行非侵入性和连续成像， 使VSV体内药效学的有意义的研究成为可能，并可能增加放射治疗 当与发射同位素131I的β粒子结合时。其他毒理学和兽医研究表明 一种安全剂量的vsv-h干扰素β-nis，可在荷瘤小鼠和病人体内安全地全身给药。 分别拥有患有自发性血液系统恶性肿瘤的犬只。 这项建议的总体目标是评估和优化系统的vsv-干扰素β-nis治疗 复发/难治性骨髓瘤患者。

Project Summary—Abstract Despite the development of novel agents for the treatment of Multiple myeloma (MM), a disseminated plasma cell malignancy, the disease remains incurable affecting ~65,000 patients in the US and causing over 10,000 deaths yearly. There is an urgent need for new, innovative therapies that can have long term impact for patients with relapsed or refractory MM. In a clinical trial at Mayo, it was recently shown that oncolytic virotherapy could induce remission in MM patients demonstrating the first successful utilization of single-shot systemic oncolytic therapy to treat disseminated cancer with minimal and short-lived clinical toxicities. We propose to build on this clinical success, utilizing a novel oncolytic agent, Vesicular stomatitis virus (VSV), an RNA virus, has several biological features making it particularly suited to treat human cancer: (i) it is a rapidly replicating, highly immunogenic virus that mediates tumor destruction by direct cytolysis and robust stimulation of antitumor immunity, (ii) Low pre-existing immunity to VSV in the general population, (iii) VSV grows to high titers allowing large-scale clinical grade virus manufacture & (iv) VSV is generally nonpathogenic in humans. Finally, myeloma cells are especially susceptible to VSV oncolysis in vitro & in myeloma mouse models. The demonstrated potent oncolytic efficacy of VSV in cancer models prompted a collaborative effort to clinically translate this promising new therapy. This has led to successful completion of preclinical toxicology studies, GMP virus manufacture, and initiation of a Phase I clinical trial evaluating intratumoral VSV-hIFNβ therapy in Hepatocellular carcinoma (HCC) patients. We have developed a novel recombinant VSV expressing Interferon-β (IFNβ) and the sodium iodide symporter (NIS), VSV-IFNβ-NIS, for intravenous (IV) treatment of disseminated myeloma. Preclinical studies showed that a single IV dose of VSV-hIFNβ-NIS is curative in an immune competent syngeneic myeloma mouse model. Murine IFNβ expression enhances tumor selectivity and stimulates antitumor immunity. NIS expression allows noninvasive and serial imaging of virus replication, enabling meaningful studies of VSV pharmacodynamics in vivo and potential addition of radiation therapy when combined with the beta particle emitting isotope 131I. Additional toxicology and veterinary studies indicate a safe dose of VSV-hIFNβ-NIS that can be safely administered systemically in tumor bearing mice and client- owned dogs with spontaneous hematologic malignancies respectively. The overall goal of this proposal is evaluation and optimization of systemic VSV-IFNβ-NIS therapy for patients with relapsed/refractory myeloma.