ONCOLYTIC VIRUS FOR HCC
A new oncolytic and immunotherapeutic vaccinia virus, JX-594 (Pexa-Vec, Jennerex Biotherapeutics), appears to significantly prolong survival in patients with advanced hepatocellular cancer (HCC), according to 2 separate studies.
In a randomized phase 2 dose-finding trial, published onlineFebruary 10 in Nature Medicine, an overall survival benefit was seen with high-dose JX-594, compared with with low-dose JX-594 (median, 14.1 vs 6.7 months; hazard ratio [HR], 0.39; P = .020). At both doses, JX-594 led to a reduction in tumor size and decreased blood flow in tumors.
"The treatment options for advanced HCC are limited, with few promising agents currently in development," said colead author Tony Reid, MD, PhD, professor of medicine at the University of California, San Diego, in a statement. This study "highlights the unique possibility of a meaningful survival benefit combined with short-term, transient, and manageable side effects.... The findings also showed [JX-594]'s ability to induce antitumor immunity and reduce blood flow to tumors, which supports [JX-594]'s multipronged approach to attacking cancer," he added.
In a phase 2 clinical study, published online February 7 in Cancer Research, it was confirmed that antiangiogenesis plays a part in the multipronged anticancer activity of JX-594. Phase 2 clinical trials have found disruption of tumor perfusion in injected tumors and tumors distant from injection sites in as soon as 5 days after treatment in patients with advanced HCC. Toxic effects related to normal blood vessels or to wound healing were not evident clinically or on magnetic resonance imaging scans.
These remarkable findings validate and provide detail on the mechanism of action of JX-594, explained lead author Caroline Breitbach, PhD, director of clinical and translational research at Jennerex, in a release. On the basis of this research, "it is clear that [JX-594] selectively targets and infects tumor-associated endothelial cells, as well as cancer cells, resulting in disruption of the blood supply and destruction of the tumor, a finding that has not been reported in patients with similar agents," she added.
Dose-Finding Results
Oncolytic immunotherapies are designed to selectively replicate within cancer cells and, subsequently, to lyse them, Dr. Reid and colleagues explain. JX-594 is designed to induce virus-replication-dependent oncolysis and tumor-specific immunity, and to disrupt the "viral thymidine kinase gene for cancer selectivity and insertion of human granulocyte-macrophage colony-stimulating factor (hGM-CSF) and beta-galactosidase transgenes for immune stimulation and replication assessment, respectively," they note.
The complete response of bulky tumors and systemic efficacy was seen in phase 1 trials of JX-594.
In this phase 2 trial, 30 patients with advanced HCC received 1 of 2 injections into liver tumors on days 1, 15, and 29: low-dose JX-594 (108 pfu) or high-dose JX-594 (109 pfu).
Kaplan–Meier survival estimates were significantly longer in the high-dose group than in the low-dose group at 1 year (66% vs 23%) and at 18 months (35% vs 11%). Survival did not correlate with the origin of the tumor.
In the 19 patients with multiple tumors at baseline (10 in the high-dose group and 9 in the low-dose group), median overall survival was longer in the high-dose group (13.6 vs 4.3 months; HR, 0.19; P = .018).
Median survival in patients with multiple tumors was half that of patients with single tumors (8.8 vs 16.6 months). The authors note that there was no correlation between survival duration and the presence of detectable neutralizing antibodies to the vaccinia virus at baseline, compared with the absence of such antibodies (HR, 0.68)
Both doses of JX-594 were generally well tolerated, Dr. Reid and colleagues report, and there were no treatment-related deaths. One patient in the high-dose group experienced a treatment-related serious adverse event (nausea and vomiting requiring prolonged hospitalization), and 8 patients (4 in each group) experienced nontreatment-related serious adverse events.
Antiangiogenesis Results
In the phase 2 antiangiogenesis trial, Dr. Breitbach and colleagues tested the hypothesis that a vaccinia virus engineered to target cells that activate the ras/MAPK signaling pathway would specifically infect and express transgenes (hGM-CSF, beta-galactosidase) in tumor-associated vascular endothelial cells in humans.
Preclinical research in mice demonstrated that an intravenous infusion of JX-594 resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours, and massive tumor necrosis within 5 days. In a phase 1 clinical trial, an intravenous infusion of JX-594 showed dose-dependent endothelial cell infection in tumors.
Dr. Breitbach and colleagues found that JX-594 disrupted perfusion to the tumor as soon as 5 days after treatment in both VEGF-receptor inhibitor-naïve and -refractory patients with advanced HCC.
This "technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically," they note.
Funding for the dose-finding study was provided by Jennerex, Transgene SA, and the Green Cross Corporation. Several coauthors report receiving individual grants, as detailed in the paper.
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