A bacterium that is naturally toxic to cattle, sheep, and humans can be tweaked to fight difficult-to-treat cancer tumors.
The modified version of Clostridium novyi bacterium produced strong and precisely targeted results in cancers in rats, dogs, and now a human subject, scientists report.
Before injecting spores into tumors in test subjects, researchers removed one of the bacterium’s toxin-producing genes to make it safer for therapeutic use, though it still caused side effects.
“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,” says Shibin Zhou, associate professor of oncology at Johns Hopkins Kimmel Cancer Center.
In its natural form, C. novyi is found in the soil and can contaminate open wounds and cause tissue-damaging and potentially fatal infection in grazing animals and humans.
The microbe thrives only in oxygen-poor environments. That makes it suitable for destroying oxygen-starved cells in tumors that are difficult to treat with chemotherapy and radiation; at the same time, it spares nearby healthy, oxygen-rich tissue.
Early immunotherapy
For a new study published in Science Translational Medicine, researchers tested direct-tumor injection of modified C. novyi spores in 16 pet dogs being treated for naturally occurring tumors. Within 21 days, tumors were eradicated in three dogs and shrunk by at least 30 percent in three others.
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Most of the dogs experienced side effects typical of a bacterial infection, such as fever and tumor abscesses and inflammation.
In a Phase I clinical trial at MD Anderson Cancer Center, a patient with an advanced soft tissue tumor in the abdomen received the spore injection directly into a metastatic tumor in her arm. The treatment significantly reduced the tumor in and around the bone, but with side effects similar to those the dogs experienced.
Zhou and colleagues 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. That treatment evolved from the observation that some cancer patients with serious bacterial infections showed cancer remission.
Verena Staedtke, a Johns Hopkins neuro-oncology fellow, first tested the spore injection in rats with implanted brain tumors called gliomas. Microscopic evaluation of the tumors showed that the treatment killed tumor 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 tumor was implanted, compared with an average of 18 days in rats that did not receive spore injection.
The researchers extended their tests to dogs because their cancer has many genetic similarities with human tumors. Dogs are also treated with many of the same cancer drugs as humans and respond similarly.
Combined treatments
Study of the spore injection in humans is ongoing, and final results are not yet available, Zhou says.
“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,” he says.
It may be possible to combine traditional treatments like chemotherapy with the modified C. novyi therapy, Zhou says. He and colleagues have already studied these combinations in mice.
Previous studies in mice suggest that modified C. novyi may help create a lingering immune response that fights metastatic tumors long after the initial bacterial treatment, but this effect remains to be seen in the dog and human studies.
Researchers from Johns Hopkins, BioMed Valley Discoveries Inc., MD Anderson Cancer Center; Animal Clinical Investigation LLC, the Veterinary Cancer Center, VCA Great Lakes Veterinary Specialists, Friendship Hospital for Animals, BluePearl Veterinary Partners, Veterinary Specialty Hospital of San Diego, City of Angels Veterinary Specialty Center and Southern Arizona Veterinary Specialty and Emergency Center contributed to the study.
BioMed Valley Discoveries, the Virginia and D.K. Ludwig Fund for Cancer Research, the Maryland Cigarette Restitution Fund, the Commonwealth Fund, Swim Across America, the Burroughs Wellcome Career Award for Medical Scientists, Voices Against Brain Cancer, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins Clinician Scientist Award, the National Cancer Institute, and the National Institute of Neurological Diseases and Stroke funded the research.
Source: Johns Hopkins University
