A Herpes Oncolytic Virus Can Be Delivered Via the Vasculature to Produce Biologic Changes in Human Colorectal Cancer

Abstract

Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates 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 x 10(6) to 1 x 10(8) particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, 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 10(8) level showed a 39% radiologic decrease in tumor size by cross-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 the human bloodstream to produce selective infection of tumor tissues and biologic effects.

A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer

“…A doseescalation study in 2006 showed that NV1020 could be safely and feasibly injected into the hepatic artery to treat colon liver metastases, 5 and a study in 2009 reported some efficacy with NV1020. 6 However, these HSV mutants are artificially and genetically modified viruses, and some have a weak replication capacity and are easily cleared by the host immune system. In contrast to artificially modified HSV mutants, HF10 is a naturally mutated virus that was derived from the parent virus strain HF, which forms syncytia, that is, fused cells.…”

Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes

“…7 In addition, several HSV mutants, including HF10, G207, 1716 and NV1020, have demonstrated both safety and efficacy in clinical trials. 7,[12][13][14][15] Patients with disseminated metastases of cancer frequently have other systemic metastases in tissues including the liver and lungs, and it is very important to deliver the viruses systemically to these metastatic sites. 17 However, Kulu et al 18 reported that i.p.…”

“…7 To date, numerous viruses, including adenovirus, HSV and Newcastle virus, have been used in clinical trials. [8][9][10][11][12][13][14][15] Clinical trials and preclinical studies with adenovirus and HSV have indicated that direct intratumoral injections of oncolytic viruses yield significant therapeutic effects. 16 However, in patients with disseminated metastases, the virus must be systemically delivered via an intravenous (i.v.)…”

Advance in herpes simplex viruses for cancer therapy

“…Physical barrier such as extracellular matrix and host immune response against HSV inhibit virus replication and distribution [17]. Clinical experiment has demonstrated that intravascular delivery of HSV is a safe and effective way to produce oncolytic effects [18]. Types of HSV used as oncolytic viruses are summarized in Table 1.…”