Synergistic Interaction Between Oncolytic Viruses Augments Tumor Killing

Abstract

A major barrier to all oncolytic viruses (OVs) in clinical development is cellular innate immunity, which is variably active in a spectrum of human malignancies. To overcome the heterogeneity of tumor response, we combined complementary OVs that attack cancers in distinct ways to improve therapeutic outcome. Two genetically distinct viruses, vesicular stomatitis virus (VSV) and vaccinia virus (VV), were used to eliminate the risk of recombination. The combination was tested in a variety of tumor types in vitro, in immunodeficient and immunocompetent mouse tumor models, and ex vivo, in a panel of primary human cancer samples. We found that VV synergistically enhanced VSV antitumor activity, dependent in large part on the activity of the VV B18R gene product. A recombinant version of VSV expressing the fusion-associated small-transmembrane (p14FAST) protein also further enhanced the ability of VV to spread through an infected monolayer, resulting in a "ping pong" oncolytic effect wherein each virus enhanced the ability of the other to replicate and/or spread in tumor cells. Our strategy is the first example where OVs are rationally combined to utilize attributes of different OVs to overcome the heterogeneity of malignancies and demonstrates the feasibility of combining complementary OVs to improve therapeutic outcome.

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

“…For survival studies, mice were culled when tumours had reached 1,600 mm 3 . For in vivo imaging, an IVIS (Perkin Elmer, Waltham, MA) was used as described previously 44 . Briefly, 100 ml of a 10-mg ml À 1 D-Luciferin solution in PBS was injected into mice i.p.…”

Model-based rational design of an oncolytic virus with improved therapeutic potential

“…However, the extent of the IFN response deficit in cancers is highly variable and can impair the efficacy of OV therapies 8 . This has led to intensive efforts aiming at suppressing IFN signalling in tumour cells without compromising the antiviral programmes in normal tissues 9,10 . Although previous mathematical models have been developed to describe the kinetics of OV replication [11][12][13][14] , the field of OV engineering has yet to adopt approaches from Synthetic Biology, where mathematical models are often used to guide the development of biological systems.…”

Stratégies génétiques, immunologiques et pharmacologiques au service d’une nouvelle génération de virus anticancéreux

“…Des traitements associant des virus oncolytiques à la radiothérapie ou combinant plusieurs virus oncolytiques sont en cours d'évaluation préclinique [33,34]. De nombreux groupes s'orientent aussi vers l'utilisation combinée de virus oncolytiques avec des composés pharmaceutiques.…”