Intracarotid delivery of oncolytic HSV vector G47Δ to metastatic breast cancer in the brain

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Abstract
Delivery of viral vectors to tumors in the brain is a challenge, especially via systemic administration, which is key to targeting the invasive margins of malignant glioma and the multiple foci of metastatic disease. Like for other cancer therapeutics, the blood–brain barrier or even the blood–tumor barrier significantly limits delivery and efficacy. Blood–brain barrier disruption (BBBD) is one strategy for transiting the cerebrovasculature. G47Δ is a third-generation oncolytic replication-competent herpes simplex virus (HSV) vector, containing deletions of the γ34.5 and α47 genes and an inactivating LacZ insertion in UL39 (ICP6). Intracarotid artery delivery of G47Δ after BBBD with 25% mannitol significantly extended the life of nude mice bearing intracerebral human MDA-MB-435 breast tumors, whereas, G47Δ injection contralateral to the tumor, in the absence of mannitol or mannitol alone had no effect on survival. G47Δ replication was extensive after BBBD, as visualized by X-gal staining. Staining of peripheral organs, lung and liver, was minimal and not altered by BBBD. This is the first demonstration of intracarotid arterial delivery of oncolytic HSV vectors and antitumor efficacy in a mouse model and opens the door to the use of mouse syngenic tumor models and transgenic/knockout animals.