Retargeted and multi-cytokine armed herpes virus is a potent cancer endovaccine for local and systemic anti-tumor treatment in combination with anti-PD1

Abstract Oncolytic viruses (OVs) are novel anti-tumor agents with the ability to selectively infect and kill tumor cells while sparing normal tissue. Beyond tumor cytolysis, OVs are capable of priming an anti-tumor immune response via lysis and cross-presentation of locally expressed endogenous tumor antigens, acting as an ‘endovaccine’. Effectiveness of OVs, like other immunotherapies, can be hampered by an immunosuppressive tumor microenvironment. Here, we modified a previously generated oncolytic herpes virus (oHSV) re-targeted to hHER2 tumor molecule and encoding mIL-12, by insertion of a second immunomodulatory molecule, mGM-CSF, to maximise therapeutic efficacy. We assessed the efficacy of this double-armed virus (R-123) compared to singly-expressing GM-CSF and IL-12 oHSVs in tumor bearing mice. While monotherapies were poorly effective, combination with α-PD1 enhanced the anti-tumor response, with the highest efficacy of 100% response rate achieved by the combination of R-123 and α-PD1. Efficacy was T cell-dependent and the induced immunity was long lasting and able to reject a second contralateral tumor. Importantly, systemic delivery of R-123 combined to α-PD1 was effective in inhibiting the development of tumor metastasis. As such, this approach could have a significant therapeutic impact paving the way for further development of this platform in cancer immunotherapy.