Complement depletion facilitates the infection of multiple brain tumors byan intravascular, replication-conditional herpes simplex virus mutant

Intravascular routes of administration can provide a means to target gene- and virus-based therapies to multiple tumor foci located within an organ, s uch as the brain. However, we demonstrate here that rodent plasma inhibits cell transduction by replication-conditional (oncolytic) herpes simplex vir uses (HSV), replication-defective HSV, and adenovirus vectors. In vitro dep letion of complement with mild heat treatment or in vivo depletion by treat ment of athymic rats with cobra venom factor (CVF) partially reverses this effect. Without CVF, inhibition of cell infection by HSV is observed at pla sma dilution as high as 1:32, while plasma from CVF-treated animals display s anti-HSV activity at lower dilutions (1:8). When applied to the therapy o f intracerebral brain tumors, in vivo complement depletion facilitates the initial infection (assayed at the 2 day time point) by an intra-arterial re plication-conditional HSV of tumor cells, located within three separate and distinct human glioma masses. However, at the 4-day time point, no propaga tion of HSV from initially infected tumor cells could be observed. Previous ly, we have shown that the immunosuppressive agent, cyclophosphamide (CPA), facilitates the in vivo propagation of an oncolytic HSV, delivered intrava scularly, within infected multiple intracerebral masses, by inhibition of b oth innate and elicited anti-HSV neutralizing antibody response (K. Ikeda e t al., Nat. Med. 5:881-889, 1999). In this study, we thus show that the add ition of CPA to the CVF treatment results in a significant increase in vira l propagation within infected tumors, measured at the ii-day time period. T he concerted action of CVF and CPA significantly increases the life span of athymic rodents harboring three separate and large glioma xenografts after treatment with intravascular, oncolytic HSV. Southern analysis of viral ge nomes analyzed by PCR reveals the presence of the oncolytic virus in the br ains, livers, spleens, kidneys, and intestine of treated animals, although none of these tissues displays evidence of HSV-mediated gene expression. In light of clinical trials of oncolytic HSV for malignant brain tumors, thes e findings suggest that antitumor efficacy may be limited by the host innat e and elicited humoral responses.