Final Report Summary - ONCOLYTIC-HERPES (ONCOLYTIC HERPESVIRUSES RETARGETED TO CANCER- SPECIFIC RECEPTORS) We usually see viruses as our enemies, particularly now, in pandemic COVID-19 era. Since viruses replicate particularly well in cancer cells, viruses can be engineered in the laboratory, or selected from natural mutants, to become a weapon against cancer cells – so-called oncolytic viruses. Among them, stand the oncolytic herpes simplex viruses (oHSVs), in particular the HSV known as T-VEC or OncoVEX GM-CSF, approved against some forms of melanoma.The aim of the ONCOLYTIC-HERPES project has been to genetically engineer oncolytic HSVs that infect and kill only cancer cells and have lost the ability to infect any other cell, by modifying the HSV tropism. We named them Retargeted HSVs (ReHSVs).The major accomplishments of the project were as follows.- The prototype ReHSV targets HER2 – a receptor overexpressed in breast, ovary and other tumours – destroys the HER2-positive cancer cells and fails to infect the cells usually targeted by wt-HSV. The cancer-specificity of HER2-ReHSVs does not rest on deletion of virulence genes, hence HER2-ReHSVs are “fully virulent viruses in their target cancer cells”. In mice, they do not cause any detectable off-tumor or off-target infection. The engineered HER2-ReHSVs are simultaneously “Safe and Robust”.- HER2-ReHSVs are highly effective in breaking the tolerance to tumors, and in unleashing the immunosuppression typical of cancers. The HER2-ReHSV-treated mice mount a strong immune response to the tumors. In this way, the cells infected with HER2-ReHSV serve as vaccines, and immunize mice against distant tumors. This ability is reinforced by insertion in the HSV genome of immunomodulatory genes, among which interleukin 12, that further boosts the long-term immune response to tumors. This is documented by infiltration of ReHSV-treated tumors with CD4+, CD8+, NK cells, their activation, and secretion of pro-inflammatory cytokines, including IFN-gamma. ReHSVs reduce the growth of glioblastomas which recapitulate the highly immunosuppressive phenotype of human glioblastomas. The high efficacy of HER2-ReHSV has made it possible to administer HER2-ReHSVs by intravenous route; systemically administered ReHSV exerts antitumor efficacy against metastatic tumors. This type of systemic efficacy is rather uncommon among oncolytic HSVs. Moreover, ReHSVs are a platform and can be re-addressed to selected Tumor Associated Antigens of choice. Examples are ReHSVs addressed to EGFRvIII, to PSMA, etc. - ReHSVs are close friends of checkpoint inhibitors, a recent class of immunotherapeutic agents with which ReHSVs synergize. Combination of HER2-ReHSVs with checkpoint inhibitors results in high increase in the efficacy of each of the two treatments: ReHSVs render checkpoint resistant tumors sensitive to checkpoint blockade, a property shared with other oncolytic viruses.-We solved the issue of how to grow and produce ReHSVs. We generated a producer cell line, namely a Vero cell derivative to which the retargeted oncolytic HSVs are re-addressed, and which supports the growth of ReHSVs for the ultimate production of clinical grade stocks under GMP production.The discoveries made in the ONCOLYTIC-HERPES project are protected by three patents, which have entered the national phases.Altogether, key steps were made towards the translation and development of clinically suited retargeted oncolytic HSVs.
