Oncolytic myxoma virus is effective in murine models of triple negative breast cancer despite poor rates of infection.

Oncolytic viruses are being heavily investigated as novel methods to treat cancers; however, predicting their therapeutic efficacy remains challenging. The most commonly used predictive tests involve determining the in vitro susceptibility of a tumor's malignant cells to infection with an oncolytic agent. Whether these tests are truly predictive of in vivo efficacy, however, remains unclear. Here we demonstrate that a recombinant, oncolytic myxoma virus shows efficacy in two murine models of triple negative breast cancer despite extremely low permissivity of these models to viral infection. These data demonstrate that in vitro infectivity studies are not an accurate surrogate for therapeutic efficacy and suggest that other tests need to be developed.

TNF blockade enhances the efficacy of myxoma virus-based oncolytic virotherapy.

BACKGROUND: Oncolytic virotherapy (OV) represents a method to treat a variety of solid tumors by inducing antitumor immune responses. While this therapy has been extremely efficacious in preclinical models, translating these successes into human patients has proven challenging. One of the major reasons for these failures is the existence of immune-regulatory mechanisms, which dampen the efficacy of virally induced antitumor immunity. Unfortunately, the full extent of these immune-regulatory pathways remains unclear. METHODS: To address this issue, we generated a doubly recombinant, oncolytic myxoma virus which expresses both a soluble fragment of programmed cell death protein 1 (PD1) and an interleukin 12 (IL-12) fusion protein (vPD1/IL-12 (virus-expressing PD1 and IL-12)). We then tested the molecular impact and therapeutic efficacy of this construct in multiple models of disseminated disease to identify novel pathways, which are associated with poor therapeutic outcomes. RESULTS: Our results demonstrate that vPD1/IL-12 causes robust inflammation during therapy including inducing high levels of tumor necrosis factor (TNF). Surprisingly, although expression of TNF has generally been assumed to be beneficial to OV, the presence of this TNF appears to inhibit therapeutic efficacy by reducing intratumoral T-cell viability. Likely because of this, disruption of the TNF pathway, either through genetic knockout or antibody-based blockade, significantly enhances the overall outcomes of vPD1/IL-12-based therapy that allows for the generation of complete cures in normally non-responsive models. CONCLUSIONS: These data suggest that some aspects of OV-induced inflammation might represent a double-edged sword during therapy and that specific blockade of TNF might enhance the efficacy of these treatments.