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Aug 14, 2014

Shrinking Tumors with Injections of Engineered Bacteria

Shrinking Tumors with Injections of Engineered Bacteria

In this stained section from C. novyi-NT-treated dog tumor, light pink denotes tumor necrosis next to areas with viable tumor cells. Black: calcified areas. [David L. Huso and Baktiar Karim, Johns Hopkins Department of Pathology]

  • Inspired by hundred-year-old accounts of how bacterial infections coincided with cancer remissions, scientists have shown that injections of a weakened bacterium—Clostridium novyi—can shrink tumors in rats and pet dogs. The scientists, based at Johns Hopkins and BioMed Valley Discoveries, even reported success in treating a human patient.

    Their approach updates early work that had been carried out in the 1890s by cancer researcher William Coley, who noticed that some patients who developed postsurgical infections went into remission or were even cured of their cancer. Coley developed treatments based on mixtures of killed bacteria, but failed to win the confidence of his peers, who questioned whether “Coley’s toxins” were effective or even safe. While other researchers revived Coley’s general approach over the decades, citing the potential cancer-fighting benefits of instigating a heightened immune response, the results were mixed at best.

    But now, scientists have published results indicating that injected bacteria can eradicate neoplastic tissues. These scientists assert that tumor eradication proceeds with such precision that further clinical trials of this agent in selected patients are warranted.

    The results were published online August 13 in Science Translational Medicine, in an article entitled, “Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses.”

    The advantage of using Clostridium novyi is that it thrives only in oxygen-poor environments, such as those prevailing deep within tumors. These troublesome spots lack the blood and oxygen needed for traditional therapies to work. But where chemotherapy and radiation struggle to have an effect, hypoxia-tolerant microbes may mount an infection and induce a strong immune response. Even better, the microbes may stop when they reach healthy tissue.

    In their study, the researchers introduced several innovations: They removed one of the Clostridium novyi bacterium’s toxin-producing genes to make C. novyi-NT, which is safer for therapeutic use. They elected to inject bacterial spores directly into tumors rather than rely on the intravenous route. (In earlier studies, few bacterial spores that had been injected into experimental animals actually reached tumors.) Finally, they expanded their investigation beyond rats.

    “It is well known that experimental models often do not reliably predict the responses of human patients to therapeutic agents,” wrote the authors. “We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations.”

    The researchers tested direct-tumor injection of the C. noyvi-NT spores in 16 pet dogs that were being treated for naturally occurring tumors. Six of the dogs had an antitumor response 21 days after their first treatment. Three of the six showed complete eradication of their tumors, and the length of the longest diameter of the tumor 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 tumor abscesses and inflammation.

    “On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores,” the researchers continued. “This treatment reduced the tumor within and surrounding the bone.”

    Studies in other patients are currently underway at multiple sites to test the safety and efficacy of this new approach. Though these results are preliminary, the researchers believe that C. novyi-NT could potentially become part of a new arsenal of immunotherapies that prime a patient’s immune system to fight off cancer.

    “Earlier preclinical studies showed that in the process of destroying cancer tissue, C. novyi-NT generates a potent innate immune response, which also contributes to the localized tumor destruction,” said Saurabh Saha, M.D., Ph.D., a senior author of the study and a longtime researcher at BioMed Valley Discoveries. "The hope is that C. novyi-NT will be a useful adjuvant to the new immune checkpoint inhibitors that can block the ability of tumors to evade a host-mediated immune response. It will be interesting to see if a combination of the two approaches could destroy tumors not just at the injection site, but also at any other sites where the cancer may have spread to throughout the body."


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