Oncolytic Virotherapy for Multiple Myeloma using VSV

项目摘要-摘要 尽管开发了用于治疗多发性骨髓瘤（MM）的新型药物，但在多发性骨髓瘤（MM）中， 细胞恶性肿瘤，这种疾病仍然无法治愈，影响约65，000名患者在美国和造成超过10，000 每年死亡。迫切需要新的、创新的疗法，这些疗法可以对癌症产生长期影响。 在马约的一项临床试验中，最近显示溶瘤药物 病毒治疗可以诱导MM患者缓解，首次成功利用单次注射 全身溶瘤治疗以治疗播散性癌症，具有最小和短暂的临床毒性。我们 我建议在此临床成功的基础上，利用一种新的溶瘤剂，水泡性口炎病毒（VSV）， RNA病毒具有几个生物学特征，使其特别适合于治疗人类癌症：（i）它是一种快速的肿瘤抑制剂， 一种复制型、高免疫原性病毒，通过直接细胞溶解和强刺激介导肿瘤破坏 抗肿瘤免疫力，（ii）一般人群中对VSV的低预先存在的免疫力，（iii）VSV生长到高水平 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对VSV溶瘤作用特别敏感。 VSV在癌症模型中表现出的强效溶瘤功效促使了合作努力， 临床上转化为有前途的新疗法。这导致成功完成了临床前毒理学 研究、GMP病毒生产和启动评价瘤内VSV-hIFN β的I期临床试验 肝细胞癌（HCC）患者的治疗。我们已经开发了一种新的重组VSV表达 干扰素-β（IFN β）和钠碘转运体（NIS），VSV-IFN β-NIS，用于静脉（IV）治疗 播散性骨髓瘤临床前研究表明，VSV-hIFN β-NIS单次静脉给药可治愈 免疫活性同基因骨髓瘤小鼠模型。小鼠IFN β表达增强肿瘤选择性 并刺激抗肿瘤免疫。NIS表达允许病毒复制的非侵入性和连续成像， 能够进行有意义的VSV体内药效学研究，并可能增加放射治疗 当与β粒子发射同位素131 I结合时。其他毒理学和兽医研究表明 安全剂量的VSV-hIFN β-NIS可以安全地全身给药于荷瘤小鼠和受试者， 自发性血液恶性肿瘤的犬。 本提案的总体目标是评价和优化系统性VSV-IFN β-NIS治疗， 复发性/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.