The Yale concept, reported in the Oct. 15 issue of the scientific journal Cancer Research, and licensed to Vion Pharmaceuticals Inc. in New Haven, Conn., involves the use of engineered strains of the common Salmonella bacterium, the same bacterium that, in its unaltered or wild type form, can cause food poisoning and septic shock. The altered Salmonella, stripped of its pathogenicity, is nonetheless able to target solid tumors in laboratory animals in a similar manner to its wild-type parent, according to John M. Pawelek, Ph.D., senior research scientist in dermatology and a lecturer in pharmacology at Yale.
However, the key is that the safe versions are still able to target solid tumors in laboratory animals, much like the wild type parent, while at the same time have little or no adverse effects. "In fact," states Dr. Pawelek, "we can now significantly prolong the life of mice with melanoma by injecting them with our attenuated bacteria. Although as few as 10 wild type bacteria are sufficient to kill a mouse, we can inject 10 million cells of our attenuated strains and the mice show no symptoms of infection. After the Salmonella are introduced into the mouse blood stream, they seek out tumors, multiply there in great numbers, and--by mechanisms not fully understood--dramatically slow the rate of tumor growth and prolong life. Furthermore, because the bacteria amplify within the tumor itself, anti-tumor genes that we introduce genetically into the bacteria are also amplified."
Yale School of Medicine researchers John M. Pawelek, Ph.D.; David Bermudes, Ph.D., and K. Brooks Low, Ph.D., co-invented this radical new cancer therapy and worked hand-in-hand with a team of scientists from Vion Pharmaceuticals, Inc., to prepare their invention for possible clinical trials in cancer patients.
Dr. Pawelek, a cancer biologist who studies melanoma; Dr. Bermudes, a parasitologist, and Dr. Low, a bacterial geneticist who is professor of research in therapeutic radiology, started collaborating in late 1992 on this project when a University of Massachusetts colleague introduced Dr. Pawelek to Dr. Bermudes, who as a Yale associate research scientist was then working only three floors above him in the Infectious Diseases Unit at Yale. Dr. Bermudes became interested in Dr. Pawelek's thoughts on an old theory on how metastatic cancer cells seem to behave like white blood cells as they spread through the body, and encouraged Dr. Pawelek to pursue the theory experimentally.
After a few weeks Dr. Bermudes returned to Dr. Pawelek with an idea for a new type of therapy: the use of white blood cell-specific parasites to seek out cancer cells. They tested several parasites for their ability to infect human melanoma cells in culture, and soon settled on further work with Salmonella, which also readily infected the human melanoma cells in culture.
Approached because of his expertise in bacterial genetics, Dr. Low was supportive and favored testing the potential of Salmonella in this way. Within weeks, Dr. Pawelek began a sabbatical in Dr. Low's lab where the trio pursued the development of safe Salmonella as an anti-cancer vector. A few months later, they obtained their first laboratory animal data, and Dr. Terrence W. Doyle, Ph.D., vice president for research and development at Vion Pharmaceuticals, Inc., became interested in the Yale-developed technology. Vion entered into a license agreement with Yale in December 1995, assisted with the patent filing and employed Dr. Bermudes as a senior scientist. Now, several years later, the Yale-Vion data were presented at the American Association for Cancer Research meeting last April in San Diego and published Oct. 15.
The three scientists were motivated by the work of Professor Rakesh K. Jain and his colleagues at Harvard University who, through the application of engineering sciences to tumors, have shown that numerous physical barriers exist within tumors, prohibiting efficient delivery of anti-cancer agents.
Explains Professor Pawelek, "Tumors have an irregular blood supply, with blood vessels not reaching many regions. They tend to be under positive pressure from the inside out. Jain's group and others have shown that these characteristics present barriers that inhibit viruses, antibodies and drugs from reaching the inner-most portions of the tumors. In contrast, Salmonella, which can move by their own swimming motion, are less subject to physical constraints and can reach and then multiply within deeper areas. When Salmonella particularly are armed with anti-cancer genes, they have the potential to kill tumor cells in areas not easily reached by other therapeutic agents."
"Most exciting is the potential use of our technology for human cancer therapy," the three scientists agreed. "We've made the Salmonella both safe and effective for laboratory animals, and now the challenge is to do the same for humans. The safety issue seems under control, and the potential effectiveness seems highly promising."