1. INTRODUCTION

The present invention relates to oncolytic vaccinia viruses which have been modified to promote anti-tumor immunity and/or reduce host antibody response against the virus.

2. BACKGROUND OF THE INVENTION

Oncolytic viruses (OV) are viruses with replication that is naturally or engineered to be selective for tumor cells1-3. A variety of different viral backbones have been examined as OV, including strains of vaccinia virus (VV).4-11At least three separate oncolytic vaccinia vectors have completed Phase I testing, including strain vvDD.6-7The VV OV, JX-5944,12(Jennerex), has recently demonstrated highly encouraging responses in Phase II trials for hepatocellular carcinoma (HCC), including systemic tumor delivery13,14. Further, encouraging Phase III results have been reported for the herpes virus HSV OV (T-Vec, Amgen15,16) in therapy of melanoma (16% responses, compared to 2% in control arm). As such, the true potential of OVs in the treatment of cancer has begun to be revealed (beyond that of the original ONYX-015 (H-101) adenovirus strain17,18that remains the only approved OV therapy in any market19).

Despite this promise, complete responses with OV remain rare. Significantly, the first and second generation OV strains were primarily designed to destroy tumor cells through selective replication leading directly to cell lysis. Additionally, JX-594 and T-Vec both express a cytokine transgene (GM-CSF) which would be expected to boost host lymphocytes.12,14,20,21Pre-clinical studies have demonstrated the critical importance of the immune response in the therapeutic activity of oncolytic VV, with (i) mice being uniformly resistant to re-challenge following a complete response after VV therapy, indicating an absolute requirement for induction of anti-tumor adaptive immunity22; (ii) the vaccine effects of VV demonstrating greater therapeutic benefit than equivalent DC vaccines23; (iii) VV infection of the tumor producing a hallmark cytokine profile (the ‘Immunologic Constant of Rejection’24); (iv) VV therapy reducing the number of immunosuppressive cells in the tumor (MDSC, T-reg and M2 macrophages)25; (v) the immune response raised by VV therapy being capable of eradicating residual tumor and metastases well after the virus has been cleared, providing long-term immune surveillance to prevent relapse22,25,26; and (vi) in some studies it appears that robust viral replication is not actually needed for therapeutic effect27,28. Therefore, the immunotherapeutic effects of OVs, particularly VV, are at least as important as the directly oncolytic effects and that these vectors should probably be considered principally as immunotherapies.

Notably, the current clinical vectors were not designed as immunotherapeutics (beyond the expression of single cytokines) and this area has remained relatively underexplored. As such, there is huge unmet potential to enhance oncolytic vectors through optimizing their interactions with the host immune system and to create vectors capable of in situ vaccination against relevant tumor antigens. Alternatively, most traditional therapeutic cancer vaccine approaches have had limited success in the clinic especially against larger tumors, despite evidence of successful immunization29-31. Novel vaccine approaches are therefore also needed, ideally mediating induction of responses against relevant antigens in every tumor, overcoming suppression even within large tumors and enhancing T-cell homing to the tumor targets.

3. SUMMARY OF THE INVENTION

The present invention relates to “immuno-oncolytic” vaccinia viruses which have been modified to promote anti-tumor immunity and/or reduce host immune and antibody response against the virus. It is based, at least in part, on the discovery of improved inhibition of tumor growth by oncolytic vaccinia virus that has been treated with an agent that reduces the amount of glycosylation and/or treated with a sialidase enzyme (which are believed to reduce TLR2 activation and to decrease host antibody response against the virus); and/or carries modifications or deletions of viral genomic nucleic acid encoding a product that reduces T cell immunity (viral interleukin-18 binding protein); and/or carries nucleic acid encoding a product that (i) enhances cytotoxic T lymphocyte induction (TRIF) and/or (ii) reduces tumor myeloid-derived suppressor cells (MDSCs) by reducing prostaglandin E2. Accordingly, the present invention provides for immuno-oncolytic vaccinia viruses and methods of using them in the treatment of cancers.

