Genetically modified bacteria safely kill cancer cells when injected
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
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
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
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.