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

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 bloodtumor barrier significantly limits delivery and efficacy. Bloodbrain barrier disruption (BBBD) is one strategy for transiting the cerebrovasculature. G47D is a third-generation oncolytic replication-competent herpes simplex virus (HSV) vector, containing deletions of the g34.5 and a47 genes and an inactivating LacZ insertion in UL39 (ICP6). Intracarotid artery delivery of G47D after BBBD with 25% mannitol significantly extended the life of nude mice bearing intracerebral human MDA-MB-435 breast tumors, whereas, G47D injection contralateral to the tumor, in the absence of mannitol or mannitol alone had no effect on survival. G47D 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. Gene Therapy (2005) 12, 647-654.

Oncolytic Capacity of Attenuated Replicative Semliki Forest Virus in Human Melanoma Xenografts in Severe Combined Immunodeficient Mice

“…Furthermore, within lung carcinoma and melanoma xenografts, spread of replication-competent adenovirus is restricted, similar to what was observed here (26,45). Incomplete transduction of tumors and tumor xenografts has been observed for a variety of replication-competent viruses, including attenuated measles virus (46,47), herpes simplex virus (48,49), and vesicular stomatitis virus (50), which suggests that physical barriers exist, which limit virus dissemination despite the ability to spread from cell to cell.…”

Vascular Distribution of Glioblastoma Multiforme at Diagnosis

“…A variety of single agents have been utilized including nitrosoureas, platinum analogs, 5-FU, etoposide, or in combination with systemic chemotherapy 3 . IA administration techniques have also been used to deliver adenoviral 4 or HSV 5 vectors to human brain tumors in mice and rats with some evidence of inhibition of tumor growth. More recently, molecularly targeted therapies such as bevacizumab, a monoclonal antibody against VEGF, and cetuximab, an antibody against EGFR, has safely been delivered by IA infusion 6,7 .…”

Herpes simplex virus delivery to orthotopic rectal carcinoma results in an efficient and selective antitumor effect

“…Because of deletion of the g34.5 and ICP6 genes, HSV-G47D replicates preferentially in cancer cells while sparing neurons and other normal cells, and therefore would be safer for in vivo use. 9,10 The histological specimen of the infected tissues presented in Figure 1b demonstrated that both HSV-1(Gb) and the attenuated HSV-G47D infected equally well the human colon carcinoma tissue while sparing the healthy colon. The efficiency of infection by HSV-1(Gb) and HSV-G47D, and their tropism to the colon carcinoma tissue suggest that they may be suitable vectors for colon carcinoma applications.…”