Radioactive microbes used on tumor cells

Despite the advances made against many types of cancer, pancreatic cancer remains grimly resistant to treatment.

Only about 4 percent of patients survive for five years, mainly because of the disease’s vicious ability to metastasize, or spread to other parts of the body. Now, a group of researchers has hit upon a novel way to halt its spread: delivering radiation directly to the cancer cells using genetically modified bacteria. In a study of mice carrying human tumors, the therapy shrank the rodent’s primary tumors while sparing healthy tissue; it also blasted cancer cells that had spread throughout the animals, reducing their number by up to 90 percent.

The cancer-targeting microorganism, Listeria monocytogenes, is a rod-shaped bacterium that penetrates the cells of the people and animals that it infects. Although the pathogen can cause severe illness, such as meningitis, a healthy person’s immune system can usually destroy it before any damage is done. Because of the bacterium’s ability to burrow inside key immune cells called macrophages, some researchers use weakened Listeria with bits of tumor DNA attached to teach the body’s immune system to recognize and destroy cancerous cells that might otherwise slip by unnoticed.

As part of this effort, immunobiologist Claudia Gravekamp, then at the California Pacific Medical Center Research Institute in San Francisco, was studying such an attenuated Listeria-based vaccine in mice carrying a highly aggressive, metastatic form of breast cancer. In 2009, Gravekamp and her colleagues found that the bacteria did more than spur the immune system to attack the cancer cells. The microbes infected and killed the cancer cells directly, while having no effect on healthy tissue. Encouraged by these results, the scientists wondered if Listeria could be used to deliver cancer-fighting therapies straight to tumor cells, including metastatic ones.

Moving to the Albert Einstein College of Medicine in New York City, Gravekamp teamed up with radiobiologist Ekaterina Dadachova and colleagues to combine modified Listeria with the radioactive compound rhenium-188, which they attached to an engineered protein called a monoclonal antibody that sticks to the bacterium. Over the course of 16 days (including a weeklong break), they injected mice already infected with a highly metastatic form of pancreatic cancer with the “labeled” bacteria. The radioactive bacteria treatment reduced the number of metastatic cells by 90 percent compared with mice given a saline solution, the team reported online in the Proceedings of the National Academy of Sciences. The attenuated Listeria alone decreased metastatic cells by 50 percent. The treatment’s effect on the original tumor was less dramatic, but still impressive: The combination of Listeria and radiation shrank the tumor by 64 percent, and Listeria alone by about 20 percent compared with saline-treated mice.

There was also very little damage to healthy tissue. The treatment’s extreme precision results from its ability to turn the cancer cells’ own defenses against them, Gravekamp explains. In healthy tissue, the immune system swiftly clears out the modified bacteria. Cancer cells, however, have ways of shutting down immune activity in their vicinity. For example, they produce proteins called cytokines that tell infection-fighting immune cells to back off and recruit “suppressor” cells directly from the bone marrow that help cancel the immune attack.

“By turning off the immune cells that would have protected them, the cancer cells make themselves uniquely vulnerable to the treatment,” Gravekamp says. “We envision this approach as a second-line therapy, which would follow either surgery or radiation to remove the primary tumor,” she says.

Co-author Dadachova adds that although a 90 percent reduction in metastatic cells is impressive, the remaining 10 percent are still potentially fatal. She believes that it’s possible to get the success rate to 100 percent, by using longer-lasting forms of radiation.

“This is an innovative and promising approach for a bad, bad disease,” says Fred Gorelick, a clinician and researcher at Yale University who specializes in diseases of the pancreas. He cautions, though, that some issues should be addressed in further research to make the treatment a realistic approach for humans.

For example, although early clinical trials of Listeria-based vaccines have shown that the neutralized bacterium produces only mild flu-like symptoms in human patients with cervical cancer, the various methods of genetically disarming the bacteria should be explored to find the safest approach for people gravely ill with pancreatic cancer, because these patients are likely to already have weak immune systems. Gorelick would also like to make sure that no dangerous levels of radiation are released as the bacteria die, noting that some buildup was seen in the kidney tissue of the mice treated in the new study.

But, he says, “the number of new cases of pancreatic cancer every year is 40,000, and the number of deaths every year is 40,000.” The prospects for that condition are bleak enough to allow for a degree of risk that might not be acceptable in less serious types of cancer, Gorelick concludes.