*4.6. Efficacy of Systemically Administered Retargeted oHSVs*

A major aim in the OV field has been the development of agents suitable for systemic treatment of metastatic cancer. Given the natural history of the viruses from which the different OVs are derived, some OVs are better suited than others for systemic administration. In addition to unspecific uptake by parenchymal organs—a barrier for all OVs, the OVs based on some human viruses, like HSV, human Adenoviruses, measles viruses need to contrast the prior immunity that exists in humans. The question arose whether retargeted oHSVs are sufficiently robust for systemic delivery. In early studies we found that a 1st

generation retargeted oHSV, named R-LM249, administered by weekly i.p. injections, significantly reduced brain and ovarian metastases by HER2-positive human tumors in immunodeficient mice carrying multiorgan tumors [56]. R-LM249 could also be delivered by means of mesenchymal carrier cells and decreased metastatic lung burden [58]. Most recently, in a immunocompetent mouse model that takes advantage of the immunotherapeutic effect, a 1st generation oHSV payloaded with IL-12 and GM-CSF, and administered in combination with anti-PD1, was capable of strongly decreasing the burden of lung tumor nodules induced by intravenous administration of LLC-1-HER2 cells, a model of metastatic lung disease [21]. Remarkably, the tumor growth inhibition occurred also in HSV-preimmunized mice [21]. The finding provides evidence that appropriately armed retargeted oHSVs in combination with checkpoint blockade can be a suitable agent for systemic administration.
