Stem Cells Turned to Weapons Against Cancer

Many researchers have an eye on stem cells for their ability to regenerate any tissue in the body. Others prefer their potential for destruction.

Khalid Shah, HMS assistant professor of radiology and neurology at Massachusetts General Hospital, and his team believe human stem cells from the patient’s bone marrow can be turned into effective weapons against cancer. They have proved in mice that human stem cells loaded with an anticancer gene successfully seek and destroy the cells of glioblastoma, the most lethal kind of brain cancer. The experimental treatment eradicated the tumor in one mouse model and extended mouse survival by over 30 percent in another.

“The whole idea is to take something that is the patient’s own and use it to deliver proteins that specifically kill tumor cells while leaving normal cells unharmed,” said Shah.

Every year, around 19,000 Americans are diagnosed with primary brain tumors that are largely incurable. Cancer cells spread rapidly across new areas of the brain, where they are difficult to hunt with surgery, radiation and chemotherapy without
damaging healthy tissue.

“The reason why we cannot cure these tumors is that they’re scattered. There is no distinct border between brain and tumor,” said Eric T. Wong, director of the Neuro-oncology Unit at Beth Israel Deaconess Medical Center.

Recent studies have shown combined radiotherapy and cancer drugs can buy patients some extra time, but life expectancy is still poor. Patients with glioblastoma live an average of a year and a half, and those with milder tumors survive for about three years, said Wong. “We are fighting a losing battle.”

The ideal treatment would be to pinpoint the tumor and kill it without causing collateral damage. That is why stem cells could be extraordinarily effective. Many researchers are using them in experimental therapies because they can develop into any kind of healthy tissue. Other scientists are more interested in the cell’s natural instinct to find trouble. Stem cells are known to travel inside blood vessels and stop wherever there is inflammation, damage and cancer. That makes them excellent tumor-seeking missiles, as John Yu, a neurosurgeon at Cedars-Sinai Medical Center in Los Angeles, explained it.

“We transplant them and we let them do what they do naturally, which is home to the tumor cells,” said Shawn Hingtgen, a postdoctoral fellow in Shah’s laboratory and co-author of the study. Their results were published online in the March 5 Proceedings of the National Academy of Sciences.

The potential of stem cells to ferry drugs had been shown before. A few years ago, Shah’s team pioneered a way to load stem cells with a secretable version of TRAIL, an antitumor gene that killed cancer cells and spared healthy ones. But Shah’s idea to use each patient’s stem cells to deliver the drug is a challenge with brain cells, which are difficult to extract. That is why he shifted to a type of stem cell from the bone marrow known as mesenchymal cells. These are not only easier to extract from patients but will also reduce the chances of causing an immune rejection when they are transplanted back in, he said.

The investigators loaded these mesenchymal stem cells with TRAIL and injected them into mice that suffered from one of the most invasive kinds of glioblastoma. The researchers also included imaging markers into both stem cells and tumor cells to track them in real time inside the brains of living mice. Five weeks later, the control mice that took hollow stem cells had bigger tumors than those injected with loaded ones. Mice undergoing the experimental fix lived up to 72 days, 18 days longer than controls. Their brains also showed the traces of dead tumor cells.

“This is clearly a good first step,” said Wong. He said the research shows promise that stem cells can kill glioblastoma without harming other brain cells. “It’s pretty encouraging.”

“The use of stem cells to deliver therapeutic molecules seems to have legs,” said Yu. He thinks this technique might be a lower hanging fruit than using stem cells for replacing damaged cells, especially in very complex tissue like the brain.

Shah believes that in the future, it might be possible to extract stem cells from a patient’s bone marrow, load them with TRAIL, and inject them back into the patient right after surgeons have extracted the bulk of the tumor. Ideally the weaponized cells would target the rest of the cancer and release their payload at the site of the tumor. Additionally, they would chase tumor cells that fled into other brain areas, he said.

But first the approach has to be honed and proven safe for humans. Shah will have to clear some common hurdles of stem cell therapies. Tumors are “intelligent,” and sooner or later they will become resistant to TRAIL, said Wong. Another frequent fear is that the stem cells might become tumors themselves. That is improbable, however, because Shah would use fresh cells without any genetic mutations. But no one knows what might happen in the long run, said Wong.

Before Shah’s team takes this technique into clinical trials, the researchers are turning different stem cell types into more versatile “missiles.” They want to load them with more molecules that will target the tumor’s blood supply, its ability to proliferate and its vulnerability all at once. “Now we have just one gene, but in the next year and a half, you will see a flurry of them coming out my lab that could be used to treat different cancer types,” he said.

Students may contact Khalid Shah at kshah@helix.mgh.harvard.edu for more information.

Conflict Disclosure: The authors declare no conflict of interest.

Funding Sources: The American Tumor Association, Goldhirsh Foundation, Alliance for Cancer Gene Therapy, American Cancer Society, and the National Institutes of Health