A Herpes Oncolytic Virus Can Be Delivered Via the Vasculature to Produce Biologic Changes in Human Colorectal Cancer
Yuman Fong1, Teresa Kim1, Amit Bhargava1, Larry Schwartz2, Karen Brown2, Lynn Brody2, Anne Covey2, Matthias Karrasch4, George Getrajdman2, Axel Mescheder4, William Jarnagin1 and Nancy Kemeny3
Department of Surgery,Memorial Sloan-Kettering Cancer Center, New York, New York, USA; 2Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; 3Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; 4 MediGene AG, Martinsried, Germany
Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and arecandidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 × 106 to 1 × 108 particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterialadministration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13–74%; P < 0.02). One of three individuals at the 108 level showed a 39% radiologic decrease in tumor size bycross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50–98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into thehuman bloodstream to produce selective infection of tumor tissues and biologic effects.
Received 18 July 2008; accepted 27 September 2008; published online 18 November 2008. doi:10.1038/mt.2008.240
candidate for a number of reasons. Because of wide human exposure, biology of HSV-1 is much studied and understood. The wild-type virus is well tolerated; most exposed patients do not demonstrateany apparent clinical syndrome. The minority of cases of clinical infection usually manifest as the common “cold sore.” The large genome of this DNA virus contains a limited number of genes that are essential for replication, leaving much room for genetic engineering to produce mutant viruses that may be even more attenuated in effects on normal tissues and may also more specifically infect andkill cancer. Furthermore, the presence of the herpes thymidine kinase (TK) gene renders this family of viruses sensitive to antivirals such as acyclovir. Thus, this class of vectors represents the only viruses under clinical investigation for which effective clinical antiviral therapy exists. Virologists have attempted to alter wild-type HSV for use as a vaccine for decades.1,2 The first HSVspecifically engineered for potential cancer therapy was reported in 1995.3 Our study represents the first vascular infusion of an engineered HSV for treatment of human disease. We had previously reported the short-term safety data related to such viral administration, demonstrating the safety of this approach.4 The current data confirm through long-term follow-up that no additional deleterious effectswere noted. In addition, these data demonstrate selective infection of tumor and biologic antitumor effects.
IntroductIon There has been great interest in exploiting the natural life cycle of herpes simplex virus type 1 (HSV-1) for killing cancer. After this virus infects host cells, it uses the host DNA and protein synthetic machinery to replicate, then kills the host cell by lysis. The...