*4.5. Retargeted oHSVs Eradicate High Grade Gliomas (HGG) in Preclinical Models*

Glioblastomas (GBMs) are among the tumors with highest resistance to surgery, chemo- and radiotherapy, and highest mortality rate. Essentially, the natural history of these tumors has not changed in the last 50 years. GBMs have been the subject of intense interest as targets of OV-based therapy, and especially of oHSVs, in part because of the natural tropism of HSV for the nervous system. Human GBMs express TAAs, such as HER-2, EGFRvIII, IL-13R2α, EGFR and others.

We provided proof of principle that GBM can potentially be treated with retargeted oHSVs. In initial studies, Malatesta and his group developed a high-grade glioma (HGG) model, consisting of human GBM cells genetically modified to express HER2 and orthotopically implanted in the brains of immunodeficient mice [57]. When the 1st generation unarmed R-LM113 was administered i.t. as single dose, it more than doubled the survival time, and fully protected about 20% of the mice [57]. These findings confirmed and extended similar finding on EGFRvIII-expressing GBM cells [49]. Subsequently, the Malatesta group developed a genetically engineered HGG preclinical model in immunocompetent syngeneic BALB/c mice. The tumors cells were derived upon overexpression of plateletderived growth factor B (PDGF-B). This model exhibits a gene expression profile typical of oligodendrocyte precursor cells and histopathological features typical of GBM, thus recapitulating GBM [66]. The cancer cells were made transgenic for HER2, and orthotopically implanted in the brains of BALB/c mice. A single dose of R-115 administered intracranially (i.c.) fully protected 30% of mice. At sacrifice, the protected mice did not harbor any remnant of tumor. Interestingly, as we observed with the LLC-1-HER2-bearing mice, all the R-115-treated mice which survived the primary tumor exhibited a long-term distant protection and developed immune response to the tumor. This consisted of a systemic IgG response, as well as of a local response, whereby tumors became infiltrated with CD4+ and CD8+ lymphocytes [60].
