Science Editor

Results from a Phase I trial of Jennerex Inc.'s experimental cancer drug JX-594, which is based on the pox virus, demonstrated that after intravenous administration of a single dose of the drug, JX-594 was able to specifically replicate in metastatic tumors. At the highest doses tested, the drug led to tumor stabilization or regression in six out of eight patients.

Clearly, there are still things to be learned about how the therapy works – the doctors saw both examples of viral replication but no tumor regression, and tumor regression but no viral replication, in their group of 23 patients overall. An accompanying commentary nevertheless called the results "a milestone."

Oncolytic therapy is partly an attempt to turn the tumor's own strategies against it. One key for the success of tumors is their undermining of immune surveillance and so interferon-gamma signaling is impaired in tumor cells.

That interferon shutoff, however, also leaves the cells open to viral infection. Jennerex, as well as several other companies, is trying to exploit that opening by using viruses to selectively infect and destroy tumor cells.

Jennerex CEO David Kirn told BioWorld Today that one of the advantages of using the modified pox virus is that it is "very good at expressing large amounts of foreign DNA." In addition to old-fashioned lysis – the bursting of tumor cells that are filled to the brim with viruses – JX-594 is engineered to express GM-CSF, which activates killer T cells. It also expresses the marker protein beta-galactosidase.

Additionally, Kirn said, the company believes it can engineer all manner of therapeutics into the virus, including antibodies or enzymes that could activate chemotherapy prodrugs selectively in cancer cells.

The modified virus, he said, is basically "a tool where one can plug in a therapeutic cassette. . . . It is similar to the iPhone, where one can have all of these different apps."

In some ways, JX-594 is the opposite of a targeted therapy: Pox virus can infect basically any epithelial cell type, and does not target any specific mutations.

The virus is "very good" at infecting epithelial cells, and potently activated by the EGF/Ras pathway, which is overexpressed in more than 90 percent of all epithelial tumors. Indeed, JX-594 gets its specificity to cancer cells from the fact that it is missing an enzyme that keeps it from replicating in normal cells.

Given JX-594's broad potential utility, Kirn hopes that it might be possible to get a broad label after demonstrating survival benefits in some number of different tumor types. For now, though, the drug is being developed in the typical manner of one tumor type at a time.

Jennerex has started JX-594 in liver cancer. "The virus loves tumors that are very vascularized and have highly overexpressed EGFR/Ras," Kirn said, both of which are true of liver tumors. Liver cancer patients treated with JX-594 have shown a survival benefit in Phase II trials. The company also is in Phase I trials with colorectal cancer and planning to test JX-594 in kidney cancer. Jennerex recently completed an $8.6 million private placement and plans to use those funds to further the drug's clinical development. Company executives said they hope to initiate Phase III trials in 2013. (See BioWorld Today, Aug. 12, 2011.)

In the current Phase I trial, whose results were published in the Sept. 1, 2011, issue of Nature, the company tested the drug in 23 patients with various metastatic solid tumors that were resistant to other treatments. The trial tested a total of six doses. At the two highest doses tested, six out of eight patients showed shrinkage or stabilization of their tumors, and seven out of eight showed evidence of viral replication. There was no evidence of JX-594 replicating in normal tissues.

Because it is not targeted, JX-594 may also be less vulnerable to the rapid development of resistance that has been the biggest drawback of targeted therapies – although Kirn noted that just because resistance might be less likely did not mean it would not develop.

"Cancer seems to always become resistant," he said. "That's why you have to hit it with multiple mechanisms."

He said that JX-594, and oncolysis in general, are a good example of using multiple mechanisms: JX-594 itself uses viral lysis and immune system activation, could be engineered to express other therapeutic proteins and can be combined with standard chemotherapy.

With such an onslaught, he said that he hopes it might be possible to eradicate tumors before they can develop resistance, though there are, of course, no guarantees: "Time will tell whether we are correct."