Researchers at the Cancer Research Center (CRC) in Columbia have discovered that they can use a genetically modified strain of Salmonella bacteria to treat or kill cancer cells.
Robert Kazmierczak, a postdoctoral fellow in biological sciences at MU, recently published a paper showing that weekly injections of a particular Salmonella strain into genetically engineered mice with prostate cancer reduced the size of the tumors without serious side-effects. Kazmierczak says this process, called bacteriotherapy, actually dates back to the late 1880s.
“There was a doctor named William Coley who was treating patients with cancer in the late 1800s. Coley observed that when treating cancer patients who had acute bacterial infections, the tumors would often shrink or go into remission,” Kazmierczak says. “He made up a mixture he called Coley’s Toxins, where he took heat-killed bacteria and injected it into people’s tumors in an attempt to get the same result.” Though there was no real way to treat cancer at the time, Kazmierczak says Coley had a few successes, but there was little interest from his peers and the idea fell out of favor. However, Coley’s research led to the development of the field of immunology.
In the 1990s, Kazmierczak says researchers conducting a vaccine study injected Salmonella into mice that had tumors, and the Salmonella seemed to target the tumor, preferentially accumulating inside the tumor. This led to a 2002 study at Yale University in which scientists developed a strain of Salmonella to treat people with non-responsive melanoma. But after a couple of weeks, the patients who had received the highest concentrations of Salmonella began to show signs of toxicity, so the study was ended.
During this same period, Abe Eisenstark, the research director at the Cancer Research Center and professor emeritus of biological sciences at MU, began testing a collection of vials of Salmonella that had been sitting on a shelf for decades. Eisenstark had gotten the collection from microbiologist Milislav Demerec, who had collected and used mutant strains of Salmonella bacteria from his colleagues in the 1950s and ’60s.
Abe Eisenstark, the research director at the Cancer Research Center and professor emeritus of biological sciences at MU.
Those strains all had single mutations that these biochemists were using to identify biochemical cycles, and they would slowly feed on whatever was left in the tube, including themselves. “What Abe did in the ’90s was break out the vials and look at the changes that had occurred over 40 years in a stored environment,” says Kazmierczak. Eisenstark and his colleagues at CRC found that despite 40 years in sealed vials, certain Salmonella strains still associated with tumor cells.
Kazmierczak, who joined the CRC in 2006, took one of the most-promising strains, CRC 1674, and engineered a number of mutations to make the strain less toxic and force it to acquire more basic nutrients from the cancer cells it was going to target in an effort to further disrupt tumors. That new strain is called CRC 2631.
What makes this strain unique? “There is only one in the world, and it’s ours,” Eisenstark says.
Kazmierczak injected mice that had been genetically engineered to develop prostate cancer while maintaining fully functioning immune systems with CRC 2631 over a number of weeks and then extracted the tumors and conducted histological analyses on them.
“All tumors are basically uncontrollably growing cells that don’t respond to the body’s commands to destroy themselves or stop growing,” Kazmierczak says. “In this case, we are turning the cancer’s own survival strategies to avoid the immune system against itself, so the Salmonella that targets and invades the tumor will not be swept up by the patient’s immune system. It can then start feeding on the tumor and spread throughout the tumor mass.”
Kazmierczak says the three-month study showed CRC 2631 did not inhibit tumor progression nor increase survival, but the Salmonella did target the tumor, and the tumor did reduce in size. He says the study showed that monotherapy—a single therapy utilizing just Salmonella —was not sufficient to treat cancer. However, Kazmierczak says the Salmonella strain CRC 2631 can be used as a “Trojan Horse” to concentrate known, effective chemotherapy drugs at the tumor site. Targeted delivery of chemotherapeutic drugs to the cancer site would ideally reduce the buildup of drugs in normal tissue, resulting in fewer adverse health effects for cancer patients.
“One major advantage of using Salmonella is that it is a bacterium, and it can make molecules itself, so it can become a molecule factory inside the tumor,” Kazmierczak says. “It can either carry chemotherapy drugs that can invade tumors with Salmonella —which is something we plan to pursue, or you can make these Salmonella produce chemotherapeutic molecules inside the tumor, which is the direction we are currently pursuing.”
Kazmierczak says the other “cool thing” about bacteriotherapy is that since it can effectively reach any cancer accessible through the circulatory system, it’s possible this form of therapy could stop the spread of cancer because it will find all secondary cancer sites in the body and target them.
He says the next phase of his project is testing different combinations of chemotherapeutics that can utilize Salmonella as a vector for carrying and delivering anti-cancer drugs to the tumors.