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

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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.