Genetically modified bacteria safely kill cancer cells when injected directly

26 August 2014

A modified version of the soil bacterium Clostridium novyi (C. novyi-NT) can produce a strong and precisely targeted anti-tumour response in rats, dogs and now humans when injected directly, according to a new report from Johns Hopkins Kimmel Cancer Center in the US.

For the study, the researchers tested direct-tumour injection of the C. novyi-NT spores in 16 pet dogs that were being treated for naturally occurring tumours. Six of the dogs had an anti-tumour response 21 days after their first treatment. Three of the six showed complete eradication of their tumours, and the length of the longest diameter of the tumour shrunk by at least 30% in the three other dogs.

Most of the dogs experienced side effects typical of a bacterial infection, such as fever and tumour abscesses and inflammation, according to a report on the work published online Aug. 13 in the journal Science Translational Medicine.

In its natural form, C. novyi is found in the soil and, in certain cases, can cause tissue-damaging infection in cattle, sheep and humans. The microbe thrives only in oxygen-poor environments, which makes it a targeted means of destroying oxygen-starved cells in tumours that are difficult to treat with chemotherapy and radiation. The Johns Hopkins team removed one of the bacteria’s toxin-producing genes to make it safer for therapeutic use.

In a Phase I clinical trial of C. novyi-NT spores conducted at MD Anderson Cancer Center, a patient with an advanced soft tissue tumour in the abdomen received the spore injection directly into a metastatic tumour in her arm. The treatment significantly reduced the tumour in and around the bone.

“She had a very vigorous inflammatory response and abscess formation,” according to Nicholas Roberts, Vet MB, PhD. “But at the moment, we haven’t treated enough people to be sure if the spectrum of responses that we see in dogs will truly recapitulate what we see in people.”

“One advantage of using bacteria to treat cancer is that you can modify these bacteria relatively easily, to equip them with other therapeutic agents, or make them less toxic as we have done here, “ said Shibin Zhou, MD, PhD, associate professor of oncology at the Cancer Center. Zhou is also the director of experimental therapeutics at the Kimmel Cancer Center’s Ludwig Center for Cancer Genetics and Therapeutics.

Zhou and colleagues at Johns Hopkins began exploring C. novyi’s cancer-fighting potential more than a decade ago after studying hundred-year old accounts of an early immunotherapy called Coley toxins, which grew out of the observation that some cancer patients who contracted serious bacterial infections showed cancer remission.

The researchers focused on soft tissue tumours because “these tumours are often locally advanced, and they have spread into normal tissue,” said Roberts, a Ludwig Center and Department of Pathology researcher. The bacteria cannot germinate in normal tissues and will only attack the oxygen-starved or hypoxic cells in the tumour and spare healthy tissue around the cancer.

Verena Staedtke, M.D., Ph.D., a Johns Hopkins neuro-oncology fellow, first tested the spore injection in rats with implanted brain tumours called gliomas. Microscopic evaluation of the tumours showed that the treatment killed tumour cells but spared healthy cells just a few micrometers away. The treatment also prolonged the rats’ survival, with treated rats surviving an average of 33 days after the tumour was implanted, compared with an average of 18 days in rats that did not receive the C. noyvi-NT spore injection.

The researchers then extended their tests of the injection to dogs. “One of the reasons that we treated dogs with C. novyi-NT before people is because dogs can be a good guide to what may happen in people,” Roberts said. The dog tumours share many genetic similarities with human tumours, he explained, and their tumours appeared spontaneously as they would in humans. Dogs are also treated with many of the same cancer drugs as humans and respond similarly.

The dogs showed a variety of anti-tumour responses and inflammatory side effects.

Zhou said that study of the C. novyi-NT spore injection in humans is ongoing, but the final results of their treatment are not yet available. “We expect that some patients will have a stronger response than others, but that’s true of other therapies as well. Now, we want to know how well the patients can tolerate this kind of therapy.”

It may be possible to combine traditional treatments like chemotherapy with the C. novyi-NT therapy, said Zhou, who added that the researchers have already studied these combinations in mice.

“Some of these traditional therapies are able to increase the hypoxic region in a tumour and would make the bacterial infection more potent and increase its anti-tumour efficiency,” Staedtke suggested. “C. novyi-NT is an agent that could be combined with a multitude of chemotherapy agents or radiation.”

“Another good thing about using bacteria as a therapeutic agent is that once they’re infecting the tumour, they can induce a strong immune response against tumour cells themselves,” Zhou said.

Previous studies in mice, he noted, suggest that C. novyi-NT may help create a lingering immune response that fights metastatic tumours long after the initial bacterial treatment, but this effect remains to be seen in the dog and human studies.