Faculty Editor: Professor Jeffrey DaCosta
Most cells require oxygen in order to properly perform aerobic cellular respiration, where glucose and oxygen are reacted to produce ATP through an intermediate. Without oxygen, most cells would die due to a buildup of electrons in the cell. Some cells, namely cancerous cells, do not require oxygen and respire anaerobically. Hypoxia, or low-oxygen levels, is common to most tumors but varies in extent across tumor types. Hypoxia is caused by structural abnormalities in the tumor, and disturbed circulation due to the haphazardly formed blood vessels in the tumor cells2. This low-oxygen environment is conducive to tumor metastasis, as the permeable vasculature facilitates the relocation of tumor cells to oxygen-rich areas of the body. Further, conventional cancer therapies such as chemotherapy and radiation rely on oxygen and the vascular system of tumor cells in order to deliver anticancer agents, so these therapies are rendered ineffective in the face of hypoxic tumor cells.
However, these hypoxic tumor areas also provide potential targets for therapeutic anaerobic bacteria, such as Clostridium novyi, as Saurabh Saha (BioMed Valley Discoveries Inc., Shibin Zhou (The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center), and their team found1. This mobile, spore-forming, oxygen-sensitive bacteria showed promise for a localized and effective agent against hypoxic tumor cells because of their ability to lyse cells. While many studies had been done on the intravenous, systemic injection of this bacterium to combat tumors, these researchers hypothesized that an intratumoral injection of spores from C. novyi may prove more advantageous as it delivers many more spores into the tumor tissue. In addition to directly destroying tumor cells, these researchers hypothesized that these spores could also elicit an adaptive immune response against the tumors as well.
Gliomas, tumors that affect the brain and central nervous system, have proven over time very difficult to treat, as they are anatomically located within a very sensitive area of the body, making surgical excision near impossible. To test their hypotheses, researchers engineered rat glioma cells to express luciferase, in order to measure tumor growth. They implanted these cells into live rats, which produced aggressive and fatal tumors. When the tumors were injected with C. novyi-NT, a derivative strain in which the primary toxin in the bacterium had been removed, the rats had a rapid fall in luciferase activity, and had a survival advantage over untreated rats. They also concluded that any potential risks in this procedure, such as brain edema and abscess formation, could be routinely managed in a medical setting.
The researchers extended their study to canine soft-tissue sarcomas (cancerous tumors of connective tissue), which are similar in histopathology to human sarcomas. 16 dogs with a diagnosis of soft-cell sarcoma, each treated with at least one and at most four cycles of C. novyi-NT-intratumoral injections, were examined after 21 days of initial treatment. In this study, there was an average of 37.5% response rate to this treatment, with some dogs having a tumor mass almost completely eradicated.
After the promising results from rats and canine tumors, the researchers expanded their study to one human trial: a 53 year old woman, diagnosed with retroperitoneal leiomyosarcoma (a rare type of sarcoma), with metastases in her liver, lungs, and soft tissue in her shoulder. The injections of the bacterium significantly reduced the tumor mass in her shoulder after only four days. After 29 days, the surgical excision of the tumor was a feasible course of treatment where it had previously not been.
These experiments are significant in that they offer an alternative approach to treating hypoxic cancers to which surgery, chemotherapy, and/or radiotherapy are ineffective forms of treatment. In addition to the treatment directly killing cells, these experiments also triggered an inflammatory response that is consistent with an innate immune response and suggests a separate non-conventional type of therapy. Although the limitations and restrictions of C. novyi-NT intratumoral injections remain to be seen in further human trials, this experiment showed promise in the eradication of some of the most aggressive forms of cancer that have been previously incurable.
- Roberts NJ, Zhang L, Janku F, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Science translational medicine. 2014;6(249):249ra111. doi:10.1126/scitranslmed.3008982
- Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83-92. doi:10.2147/HP.S93413.