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

项目总结 溶瘤病毒疗法是一种分两步进行的疗法。在溶瘤期(短暂)，感染在 肿瘤，杀死受感染的细胞，使微环境变得炎热。在免疫阶段(长时间)启动和 炎性介质和吞噬细胞碎片扩增肿瘤特异性细胞毒性T细胞(CTL) 从死亡或濒临死亡的肿瘤细胞中分离出来，可以杀死未感染的肿瘤细胞。β-NIS是一种快速复制的 溶瘤性水泡性口炎病毒(VSV)，可导致炎性肿瘤细胞死亡。在第一次骨髓瘤期间 孢子资助期，我们启动了一项研究人员发起的人类首例单剂、单剂研究 静脉注射VSV-干扰素β-NiS治疗恶性血液病有很好的耐受性和 令人鼓舞的抗肿瘤活性迹象。已经进行了广泛的相关分析来表征 抗肿瘤免疫反应的动力学，以及它们与患者特定基线参数的关系。 在第二期骨髓瘤孢子资助期，我们寻求最大限度地发挥静脉注射的效力 病毒干扰素β-nis联合(I)重复给药，(Ii)早期抑制抗病毒治疗 免疫反应，以及(Iii)联合使用免疫抑制对抗骨髓瘤T细胞的晚期促进作用 和免疫激活方案，总体目标是使用VSV病毒疗法实现持久应答 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.