Scientists at Jennerex, Inc. in San Francisco, and collaborators from University of Pennsylvania and the University of Ottawa in Canada have just engineered a poxvirus, JX-594, to selectively replicate in tumor cells that have an activated EGFR/ Ras pathway, but not in normal tissue. The poxvirus acts as a vehicle to deliver a transgene to the cancer cells that results in expression and subsequent cell lysis and anticancer immunity.
Electron micrograph of an epidermal cell with cytoplasmic degeneration and numerous poxvirus particles (V); a second cell has marginated chromatin (MC) and a filamentous matrix (F) in the nucleus, which corresponds to the central nuclear clearing seen histologically. Insert shows typical poxvirus particles. (Courtesy of D. A. Gregg.)An oncolytic viral delivery system can either supply a high concentration of a biologic for cancer treatment, or an imaging biologic directly to the tumor. In an article published in Nature (doi:10.1038/nature10358) David H. Kim, MD, Caroline J. Breitbach, PhD, and colleagues demonstrate that JX-594 selectively infects cancer tissue, replicating and expressing the transgene products within the tumor cells. The intravenous (IV) infusion of the virus did not clinically affect normal tissue and the dose-dependent effect is seen after a single intravenous injection.
As the authors highlight in the abstract, the results demonstrate the potential utility of this platform in cancer treatment. This is the first in-human demonstration of delivery and transgene expression via an oncolytic virus in metastatic solid tumors using an IV administration.
Prior to the phase I initiation, the authors demonstrated that JX-594 selectively infected ex vivo tumor tissue within 24 hours, but not normal tissue or peripheral blood mononuclear cells. The dose-escalating clinical trial aimed to test whether JX-594 could infect metastatic tumors after an IV delivery to 23 late-stage solid cancer patients.
Trial Results
JX-594 was well-tolerated and dose-limiting toxicities were not observed with drug dose-escalation. Common adverse events were flulike symptoms of fever, chills, fatigue, headache, nausea, and some hypotension, vomiting, and anorexia. IL-6 and IL-10 levels increased in patients but IL-1 levels did not change, and IL-4 levels decreased transiently. All six high-dose patients developed neutralizing antibodies to the virus but there appeared to be no correlation between antibody titers and replication, safety, or tumor activity of the compound.
JX-594 delivery and replication in tumors were confirmed in biopsies. The authors suggest that suppression of microscopic tumor foci occurred as there was less frequent new tumor growth at high compared to low doses. FDG-PET scans showed antitumor activity in two of the five high-dose patients.
JX-594 is a proprietary, engineered, vaccinia (a type of poxvirus) vaccine-derived oncoloytic virus. The researchers cite these viruses as being well suited for this use because: 1) vaccinia has evolved mechanisms for IV stability, including a resistance to antibody as well as complement-mediated neutralization in the blood system; 2) vaccinia is able to spread to different tissues and has motility within tissues; 3) the large size of the varions may preferentially distribute the virus within tumors where the new vasculature increases permeability; and 4) vaccinia virus replication depends on the EGFR/Ras signaling pathway, a pathway that's frequently mutated in epithelial cancers.
JX-594 was specifically designed to lyse cancer cells; to reduce the blood supply to tumors through the targeting and destruction of their vasculature; and to stimulate the body's immune response against the cancer cells.
The genome of the vaccinia virus in JX-594 was specifically engineered with an inactivated viral thymidine kinase (TK) gene, and expression of the human granulocyte-macrophage colony stimulating factor (hGM-CSF) and beta-galactosidase transgenes. Deleting the TK gene makes the virus dependent on cellular TK, which is expressed at high levels in cancer cells. The hGM-CSF additionally complements the cancer cell lysis pathway, which results in tumor necrosis, blockage of tumor vasculature, and an antitumor immune response. The vaccinia strain backbone has been safely used for vaccination of millions of people worldwide.
Although this phase I trial was not designed to test clinical efficacy, the results show activity at high doses in metastatic cancer patients, suggesting that further studies with JX-594 in solid tumor patients is warranted.
A previous phase I trial of intratumoral injection into liver tumors showed good tolerability and replication of the virus. A total of 100 patients with tumor types ranging from melanoma, colon, kidney, and lung cancers have been shown to respond to the treatment. JX-594 is currently in an international phase II trial in patients with primary liver cancer, alone and in combination with sorafenib(Drug information on sorafenib).
