Project 1: Optimizing a VSV-based virotherapy-based regimen for advanced MM

项目摘要 溶瘤病毒疗法是一种两阶段疗法。在溶瘤期（短暂），感染在 肿瘤，杀死受感染的细胞和发炎的微环境。在免疫阶段（延长）引发和 通过炎症介质和吞噬碎片扩增肿瘤特异性细胞毒性T细胞（CTL） 死亡或垂死的肿瘤细胞导致未感染的肿瘤细胞被杀死。VSV-IFNβ-NIS是一种快速复制的 溶瘤性水泡性口炎病毒（VSV），其导致炎性肿瘤细胞杀伤。在第一次骨髓瘤 在SPORE资助期间，我们启动了一项由研究者发起的单剂量、单药物的首次人体研究。 静脉内（IV）VSV-IFNβ-NIS治疗恶性血液病患者。具有良好的耐受性， 令人鼓舞的抗肿瘤活性迹象。进行了广泛的相关分析，以表征 抗肿瘤免疫应答的动力学及其与患者特异性基线参数的关系。 在第二个骨髓瘤孢子资助期间，我们寻求最大限度地提高静脉注射的效力。 通过联合（i）重复病毒给药，（ii）早期抑制抗病毒药物， 免疫反应，以及（iii）通过使用免疫抑制组合来晚期加强抗骨髓瘤T细胞 和免疫激活方案，总体目标是使用VSV病毒疗法在 多发性骨髓瘤患者。

PROJECT SUMMARY Oncolytic virotherapy is a two-stage therapy. In the oncolytic phase (short-lived) the infection spreads in the tumor, killing infected cells and inflaming the microenvironment. In the immune phase (prolonged) priming and amplification of tumor-specific cytotoxic T cells (CTLs) by inflammatory mediators and phagocytosed debris from dead or dying tumor cells leads to killing of uninfected tumor cells. VSV-IFNβ-NIS is a fast-replicating oncolytic Vesicular Stomatitis Virus (VSV) that causes inflammatory tumor cell killing. During the first Myeloma SPORE funding period, we launched an investigator initiated first-in-human study of single dose, single agent intravenous (IV) VSV-IFNβ-NIS in patients with hematological malignancies. There is good tolerability and encouraging signs of antitumor activity. Extensive correlative analyses have been conducted to characterize the kinetics of the antitumor immune responses, and their relationship to patient-specific baseline parameters. During the second Myeloma SPORE funding period we seek to maximize the potency of intravenous VSVIFNβ-NIS therapy by combining (i) repeat virus administration, (ii) early suppression of the antiviral immune response, and (iii) late boosting of antimyeloma T cells by using a combination of immune suppression and immune activating regimens with the overall goal to achieve a durable response using VSV virotherapy in patients with multiple myeloma.