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Recent news suggests that Canadian Cancer Specialists have found what researchers have labelled a medical first, in that an engineered virus which is injected into the cancer patients blood stream targets cancer cells throughout the body killing them, or at least not letting them get any bigger. Out of 23 patients, who have highly metabolized cancer, which means that the cancer has spread throughout their body and doesn’t show signs of being decreased, have been injected with a cancer fighting virus which hopes to kill the cancer cells. This is not the first time that a cancer virus has been suggested to the public. However, normally with cancer viruses, the virus itself had to be administered and injected directly into the tumor. This is extremely difficult as, tumors are not always stationary within the human body. The anti-cancer virus JX-594 was injected into the blood of 23 patients. 8 out of the 23 patients had the JX-594 replicating itself inside the cancer tumors, and not spreading into other healthy non-cancer cells.
"We are very excited because this is the first time in medical history that a viral therapy has been shown to consistently and selectively replicate in cancer tissue after intravenous infusion in humans.” Said, Professor John Bell, who is the lead research from the University of Ottawa. Professor Nick Lemoine, director of Barts Cancer Institute said, “Viruses that multiply in just tumor cells - avoiding healthy cells - are showing real promise as a new biological approach to target hard-to-treat cancers. This new study is important because it shows that a virus previously used safely to vaccinate against smallpox in millions of people can now be modified to reach cancers through the bloodstream - even after cancer has spread widely through the patient's body. "It is particularly encouraging that responses were seen even in tumors like mesothelioma, a cancer which can be particularly hard to treat."
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.
