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The ERC-Advanced Oncolytic-Herpes project was funded to design and develop oncolytic herpes simplex viruses (HSVs) that are highly cancer-specific and can enter clinical trials. The interest in oncolytic viruses, and, in particular, in oncolytic HSVs has greatly increased following the approval by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) of the first oncolytic HSV for clinical applications, and because they can be combined with other therapies, in particular with immune checkpoint blockade antibodies (Abs), and thus act as oncolytic immunotherapeutic agents. Our approach to highly cancer-specific oncolytic HSVs consists in the retargeting of the viral tropism to cancer-specific receptors, in our case HER2 (epidermal growth factor receptor 2), a member of the EGFR (epidermal growth factor receptor) family overexpressed in a portion of breast, ovary, stomach, lung, brain cancers. It entails the insertion of single chain antibodies (scFV) to HER2 in appropriate glycoproteins that form the entry apparatus of HSV. The latter is made of glycoprotein D (gD), gH/gL, gB, that are activated in a cascade fashion. Our initial proof-of-concept results indicated that gD accepts the insertion of scFv and enables the generation of HER2-retargeted oncolytic HSVs. We have now expanded our retargeting strategies, and have generated fully retargeted HSVs by insertion of the scFv in appropriate regions of gH, and of gB. The latter is the fusogenic glycoprotein and it was unanticipated that it might serve as the determinant of HSV tropism. Inasmuch we have now available multiple retargeting tools, we have been able to generate double retargeted HSVs. In one application, the viruses were simultaneously retargeted to HER2 and to an artificial receptor that we have expressed in non-cancer cells. This will enable the production of clinical grade o-HSV in non-cancer cells. In a second application, the oncolytic HSV targets simultaneously two different cancer receptors; this widens of spectrum of cancers that can be treated, and enables to contrast the heterogeneity in expression of the cancer receptors.
As mentioned, much of the current interest is in the development of oncolytic-immunotherapeutic viruses. To this aim, we have armed the HER2-retargeted oncolytic HSV with cytokines, such as IL-12, or immune checkpoint blockers, such as a scFv to PD-L1. Given the large genome capacity of HSV genome, these molecules can be expressed simultaneously by a same oncolytic HSV. To test the anti-cancer therapeutic effects of these oncolytic HSVs, we have developed mouse model systems. Because the HSVs are retargeted to the huHER2, mice need to be transgenic, hence tolerant to huHER2. We have now available two such murine models, from different mouse strains, and the respective murine cancer cell lines; even the latter are transgenic for huHER2.
A critical issue is whether the retargeted oncolytic HSVs can be administered by a systemic route so that they can reach metastatic disease. We have developed a strategy based on carrier cells whereby the retargeted oncolytic HSV can target and exert therapeutic effect on lung and brain metastatic disease of breast and ovary HER2-positive cancers.
Finally, the retargeting strategy developed in our laboratory enabled us to target additional cancer receptors, including EGFR, the gliobastoma variant EGFRvIII, PSMA (prostate-specific membrane antigen). These viruses are being assayed for efficacy in appropriate preclinical systems, including glioblastoma and prostate cancer models.
Together, our results have paved the way for the successful translation of the retargeted oncolytic HSVs to clinical trials.