The first purposeful vaccination program was carried out in the late 18th century, when physician Edward Jenner used cowpox as a vaccination to protect against smallpox.

Jenner had impressive faith in his ideas, though he was apparently a less astute ethicist than immunologist. He deliberately infected vaccinated children, including his 11-month-old son, with smallpox to demonstrate the efficacy of his approach.

San Francisco-based Jennerex Biotherapeutics, which was founded in 2003 and is named after Jenner, is using vaccinia virus to combat a different disease: cancer.

Luckily for their families, the company is using a more conventional route to demonstrating safety and efficacy of its products than Jenner did. Earlier this week, Jennerex presented results from Phase II trials at the American Association for Cancer Research, National Cancer Institute and European Organization for Research and Treatment of Cancer conference being held this week in San Francisco,. And in the Oct. 25, 2007 issue of the Journal of Clinical Investigation, scientists from Jennerex and academic collaborators from the U.S., South Korea and the U.K. described the engineering they used to create what they term "a broad-spectrum and systemically effective oncolytic poxvirus."

Viral oncolytics, even more than most other drugs, are caught on a narrow strait between two undesirable outcomes. If the immune system is too strong, the virus will be destroyed before it has a chance to get to the cancer cells. On the other hand, if the immune system is too weak - a fairly likely scenario in a cancer patient - the virus conceivably could get out of hand, leading to a worst-case scenario of a cancer patient with pox.

To avoid that pitfall, Jennerex is following the advice of former Lockheed Martin CEO Martin Augustine that "the best way to make a silk purse from a sow's ear is to start with a silk sow."

Kirn said "A virus is not a virus - they have very different biologies." And to get a good cancer killer, "you need to pick a virus with the biology you want."

Specifically, this means a virus that spreads rapidly, infects epithelial tissues and spends part of its life cycle in the bloodstream. After selecting a pox virus strain that met those requirements, Jennerex scientists deleted its thymidine kinase gene to prevent the virus from replicating in normal cells. In a final step, the virus was engineered to express GM-CSF, which activates killer T cells.

Jennerex has finished up a Phase I/II clinical trial with JX-594, and presented the data earlier this week at the AACR-NCI-EORTC meeting. Kirn said the results are "markedly different from what's been seen in most trials to date." Ten of 13 patients showed an objective response, with half surviving for more than eight months and two for more than a year after treatment. Kirn noted that there also was evidence that the drug targeted distant tumors through the bloodstream. "That is new for oncolytic viruses," he said.

Jennerex is initiating a Phase IIa clinical trial in the U.S. for liver cancer and planning a further Phase IIa for squamous cell head and neck cancers in early 2008. The company also plans to conduct clinical trials for patients with lung cancer and melanoma.

In their JCI paper, the researchers presented preclinical data on a second agent in their pipeline, JX-963. JX-963 is built on the same basic principle as JX-594, but was engineered from a different pox virus strain that has had an additional gene removed.

In cell culture studies, JX-963 replicated only cancer cells, and was more effective at killing those cells than the oncolytic virus Onyx-015. Onyx-015's development was discontinued in 2003 when Onyx Pharmaceuticals cut staff and development programs after its partnership with Warner-Lambert, now part of Pfizer, came to an end. (See BioWorld Today, Jan. 28, 2003, and Sept. 18, 2003.)

When JX-963 was administered to mice and rabbits, it inhibited both the growth of primary liver tumors and lung metastases.

Collectively, the results suggested that Jennerex' candidates are able to get their goods past the immune system. As for the possibility of a runaway virus, Kirn acknowledged that despite the genetic engineering designed to prevent replication in normal cells, "with any cancer therapeutic you worry about side effects - we're no different from anyone else."

But, he said, if the worst case should materialize, there are several antiviral drugs that are effective against the virus.

"We hope not to have to use them," he said. "But they are there if we need them."