Genetically Altered Salmonella Bacteria May Offer Potential Cancer Treatment

The Yale concept, reported in the Oct. 15 issue of the scientificjournal Cancer Research, and licensed to Vion Pharmaceuticals Inc. in New Haven,Conn., involves the use of engineered strains of the common Salmonellabacterium, the same bacterium that, in its unaltered or wild type form, cancause food poisoning and septic shock. The altered Salmonella, stripped of itspathogenicity, is nonetheless able to target solid tumors in laboratoryanimals in a similar manner to its wild-type parent, according to John M.Pawelek, Ph.D., senior research scientist in dermatology and a lecturer inpharmacology at Yale.

However, the key is that the safe versions are still able to target solid tumorsin laboratory animals, much like the wild type parent, while at the same timehave little or no adverse effects. "In fact," states Dr. Pawelek, "we can nowsignificantly prolong the life of mice with melanoma by injecting them with ourattenuated bacteria. Although as few as 10 wild type bacteria are sufficient tokill a mouse, we can inject 10 million cells of our attenuated strains and themice show no symptoms of infection. After the Salmonella are introduced intothe mouse blood stream, they seek out tumors, multiply there in great numbers,and--by mechanisms not fully understood--dramatically slow the rate of tumorgrowth and prolong life. Furthermore, because the bacteria amplify within thetumor itself, anti-tumor genes that we introduce genetically into the bacteria are alsoamplified."

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 andworked 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, aparasitologist, and Dr. Low, a bacterial geneticist who is professor of researchin therapeutic radiology, started collaborating in late 1992 onthis project when a University of Massachusetts colleague introduced Dr. Pawelekto Dr. Bermudes, who as a Yale associate research scientist was then workingonly 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 howmetastatic cancer cells seem to behave like white blood cells as they spreadthrough the body, and encouraged Dr. Pawelek to pursue the theoryexperimentally.

After a few weeks Dr. Bermudes returned to Dr. Pawelek with an idea for a newtype of therapy: the use of white blood cell-specific parasites to seek outcancer cells. They tested several parasites for their ability to infect humanmelanoma 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 wassupportive and favored testing the potential of Salmonella in this way. Withinweeks, Dr. Pawelek began a sabbatical in Dr. Low's lab where the trio pursuedthe 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 alicense agreement with Yale in December 1995, assisted with the patent filingand employed Dr. Bermudes as a senior scientist. Now, several years later, theYale-Vion data were presented at the American Association for Cancer Researchmeeting last April in San Diego and published Oct. 15.

The three scientists were motivated by the work of Professor Rakesh K. Jain andhis colleagues at Harvard University who, through the application of engineeringsciences to tumors, have shown that numerous physical barriers exist withintumors, prohibiting efficient delivery of anti-cancer agents.

Explains Professor Pawelek, "Tumors have an irregular blood supply, with bloodvessels not reaching many regions. They tend to be under positive pressure fromthe inside out. Jain's group and others have shown that these characteristics present barriers that inhibit viruses, antibodies anddrugs from reaching the inner-most portions of the tumors. In contrast,Salmonella, which can move by their own swimming motion, are less subject tophysical constraints and can reach and then multiply within deeper areas. WhenSalmonella particularly are armed with anti-cancer genes, they have thepotential to kill tumor cells in areas not easily reached by other therapeuticagents."

"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 effectivefor laboratory animals, and now the challenge is to do the same for humans. Thesafety issue seems under control, and the potential effectiveness seems highlypromising.&#