Abstract 4450: Therapeutic potential of cargo-armed next generation variants of VSV-GP and synergy with immune modulators
Authors: Mueller Philipp , Nolden Tobias , Erb Klaus , Petersson Monika , Stierstorfer Brigit , Heinemann Fabian , Herrmann Valerie Laura , Impagnatiello Maria Antonietta , Borges Eric , Elbers Knut , Park John , Wollmann Guido , Erlmann Patrik 
Published: September 2020

Introduction Oncolytic viruses (OVs), which selectively replicate in and destroy tumor cells, represent a highly promising class of cancer therapeutics with a strong immune stimulatory potential. VSV-GP, a chimeric Vesicular Stomatitis Virus (VSV) pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (LCMV) is a potent tumor cell-lysing agent and capable of jump-starting α-tumor immunity. The current study explores the immune promoting properties of VSV-GP and one of its cargo-armed, next generation variants with a T-cell/DC-directed MoA. It further investigates clinically relevant combination therapies with checkpoint inhibition (α-PD-1) as well as a “second mitochondria-derived activator of caspases“ mimetic (SMACm).

Experimental Procedures Immune competent mice bearing established LLC1-IFNARKO, B16-F1-OVA or CT26.CL25-IFNARKO tumors were subject to treatments comprising VSV-GP variants, α-PD-1, a SMACm or combinations of the latter. Anti-tumor effects were determined by tumor growth inhibition and/or changes in overall survival. VSV-GP´s tumor cell selective replication, resulting in immune activation as well as cargo mediated immune modulation, were assessed using FFPE based IHC staining as well as NanoString and functional in vitro assays.

Data Summary Here we present data on VSV-GP and one of its improved, next generation variants, which display potent α-tumor efficacy and upon systemic delivery increase the local T-cell and dendritic cell infiltration as well as activation within the tumor microenvironment. Building on the observed therapeutic and immune-modulatory potential of VSV-GP and its cargo-armed variant, we further explored therapeutic combinations with a PD-1 blocking antibody, which resulted in a strong improvement of the VSV-GP-mediated α-tumor efficacy. Immunological memory formation in cured animals was demonstrated by a tumor rechallange experiment. We further explored the therapeutic combination of VSV-GP and its cargo-bearing variant with a SMACm, which resulted in a strongly improved therapeutic benefit as well as increased overall survival in case of VSV-GP. The VSV-GP encoded immune-stimulatory cargo further improved this therapeutic synergy.

Conclusion In summary VSV-GP induces a pro-inflammatory microenvironment within infected tumors, increases immune cell infiltration, a feature, which is further improved by tumor selective expression of VSV-GP encoded therapeutic cargos, and synergizes with α-PD-1 as well as a SMACm. The strong α-tumor immunity promoting potential of the VSV-GP platform observed in preclinical disease models justifies further testing of VSV-GP variants and the respective therapeutic combinations in clinical trials.

Citation Format: Philipp Mueller, Tobias Nolden, Klaus Erb, Monika Petersson, Brigit Stierstorfer, Fabian Heinemann, Valerie Laura Herrmann, Maria Antonietta Impagnatiello, Eric Borges, Knut Elbers, John Park, Guido Wollmann, Patrik Erlmann. Therapeutic potential of cargo-armed next generation variants of VSV-GP and synergy with immune modulators [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4450.