Phase I, Open-Label, Dose-Escalating Study of a Genetically Engineered Herpes Simplex Virus, NV1020, in Subjects with Metastatic Colorectal Carcinoma to the Liver

Abstract

Current regimens of systemic chemotherapy result in only modest lengthening of survival in patients with advanced stage, liver-dominant, metastatic colorectal cancer who have failed first-line chemotherapy. The objective of this study was to investigate the safety and tolerability of NV1020, a replication-competent, attenuated, genetically engineered herpes simplex virus type 1 (HSV-1), in patients with hepatic colorectal metastases refractory to first-line chemotherapy. A phase I, open-label, dose-escalating study of a single 10-min hepatic arterial infusion of NV1020 in four cohorts. Three patients in each cohort received doses of 3 x 10(6), 1 x 10(7), 3 x 10(7), and 1 x 10(8) plaque-forming units. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum y-glutamyltransferase, one diarrhea, and one leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There were no deaths during the study, and there was no evidence of disseminated herpes infection. Viral presence was detected in only one saliva sample and two serum samples from one asymptomatic patient in the highest dose cohort. In the first week after viral administration only rare and minor increases were noted for tumor necrosis factor-alpha (six samples; three patients; peak, 40 pg/ml), interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and interferon-y (four samples; two subjects; peak, 54 pg/ml). No IL-2 was detected. Mild liver enzyme elevations were self-limiting and not associated with clinical symptoms. We conclude that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function.

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

“…Malignant human peripheral nerve sheath tumors are driven by mutated Ras oncogene and by overexpressed epidermal growth factor receptor signaling; xenografts of these tumors are susceptible to combined treatment with G207 and erlotinib [247]. Of twelve patients receiving through the hepatic artery replication-competent and attenuated NV1020 HSV-1 for the treatment of colorectal cancer metastatic to the liver, two experienced minor response, seven remained stable, and three progressed [199].…”

Inhibition of the IFN-β Response in Hepatocellular Carcinoma by Alternative Spliced Isoform of IFN Regulatory Factor-3

“…1 Given the limited treatment options and poor prognosis, the use of oncolytic viruses, which have the intrinsic property of selectively replicating in cancer cells and killing them, has found application in preclinical studies and early clinical trials for the treatment of primary and metastatic liver cancers. [2][3][4][5][6][7][8] Vesicular stomatitis virus (VSV), a nonsegmented negative strand RNA virus belonging to the Rhabdoviridae family, 9 is one such oncolytic virus. It represents a promising agent for cancer treatment because of its tumor selectivity and rapid replication in many tumor cell types, including HCC.…”

Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10

“…To date, various kinds of HSV mutants have been evaluated as candidates for oncolytic virotherapy [10]. Among these, G207, HSV1716, NV1020 have been tested in clinical trials with encouraging results including melanoma [29][30][31][32]. In a pilot study, HSV1716 was intratumorally injected into subcutaneous nodules of metastatic melanoma [29].…”