Pre-surgical neoadjuvant oncolytic virotherapy confers protection against rechallenge in a murine model of breast cancer

Nikolas Tim Martin,Marie-Claude Bourgeois-Daigneault,Rob C Hoeben,Dominic Guy Roy,Samuel Tekeste Workenhe,John Cameron Bell,Karen Louise Mossman,Diana J M Van Den Wollenberg

doi:10.1038/s41598-018-38385-7

Abstract

The use of oncolytic viruses (OVs) for cancer treatment is emerging as a successful strategy that combines the direct, targeted killing of the cancer with the induction of a long-lasting anti-tumor immune response. Using multiple aggressive murine models of triple-negative breast cancer, we have recently demonstrated that the early administration of oncolytic Maraba virus (MRB) prior to surgical resection of the primary tumor is sufficient to minimize the metastatic burden, protect against tumor rechallenge, cure a fraction of the mice and sensitize refractory tumors to immune checkpoint blockade without the need for further treatment. Here, we apply our surgical model to other OVs: Vesicular stomatitis virus (VSV), Adenovirus (Ad), Reovirus (Reo) and Herpes simplex virus (HSV) and show that all of the tested OVs could positively change the outcome of the treated animals. The growth of the primary and secondary tumors was differently affected by the various OVs and most of the viruses conferred survival benefits in this neoadjuvant setting despite the absence of direct treatment following rechallenge. This study establishes that OV-therapy confers long-term protection when administered in the pre-operative window of opportunity.

Highlights

The use of oncolytic viruses (OVs) for cancer treatment is emerging as a successful strategy that combines the direct, targeted killing of the cancer with the induction of a long-lasting anti-tumor immune response
These clinical findings are in line with preclinical work conducted using murine models of cancer, which demonstrated that various OVs (MRB8, Reo[12], Newcastle disease virus[13], VV14, Measles virus[15] and HSV16) could sensitize refractory tumors to immune checkpoint blockade and control the treated tumors, and natural metastases
Our results show that Maraba virus (MRB), Vesicular stomatitis virus (VSV), Ad and Herpes simplex virus (HSV) could all efficiently control the growth of secondary tumors and cure 10 to 20% of the mice

Summary

Introduction

The use of oncolytic viruses (OVs) for cancer treatment is emerging as a successful strategy that combines the direct, targeted killing of the cancer with the induction of a long-lasting anti-tumor immune response. The clinical significance of this virus-induced inflammation is supported by two different in-human studies where the regression of distant lesions following local OV-therapy was reported (Vaccinia virus (VV) for hepatocellular carcinoma[10] and HSV for melanoma[11] treatment) These clinical findings are in line with preclinical work conducted using murine models of cancer, which demonstrated that various OVs (MRB8, Reo[12], Newcastle disease virus[13], VV14, Measles virus[15] and HSV16) could sensitize refractory tumors to immune checkpoint blockade and control the treated tumors, and natural metastases. We tested 4 additional OVs: VSV, Ad, Reo and HSV and found that all but Reo could efficiently confer protection against tumor rechallenges and improve survival from 5 to 10 days

Methods

Results

Conclusion