13 February 2017

Bacteria against cancer

Maxim Rousseau, Polit.roo

Tumor cells often avoid attack from the body's immune system, as they are not recognized as foreign. To overcome this obstacle, scientists suggest infecting tumor cells with bacteria. In a recent experiment, they modified the bacterium salmonella, known for causing severe food infections, and made it infect human tumor cells transplanted into laboratory mice. This caused a strong immune response, which led to a decrease in the size of tumors and, for the first time in the history of such experiments, to the cessation of metastasis. If such a method can be reproduced in the human body, it will be a significant step forward in bacterial cancer therapy.

Doctors made observations about the positive effect of some bacterial infections on the condition of cancer patients back in the XVIII century, when it was not even known about the existence of bacteria. It was noted that the so–called erysipelas - an infectious inflammation with a characteristic redness of the skin, can lead to a slowdown in the growth of the tumor or even its reduction. Dr. Anton Chekhov told about this phenomenon in a letter to Suvorin dated December 24, 1890: "Cancer is not a microbe; it is a tissue growing out of place and, like chaff, drowning out all neighboring tissues. If the Gay man's uncle has become easier, it only means that the cochin, as an integral part, includes erysipelas, i.e. elements that produce erysipelas disease. It has long been noticed that for some reason the growth of malignant tumors temporarily stops with erysipelas."

The first experience of targeted use of bacteria against cancer dates back to the end of the XIX century. Then the American surgeon William Coley (1862 – 1936) proposed an "anti-cancer vaccine" based on bacteria Streptococcus pyogenes (the causative agent of scarlet fever) and Serratia marcescens (responsible for part of the so-called nosocomial infections of the respiratory and urinary tract). William Coley found several medical histories where patients with severe cancer were cured by suffering a bacterial infection. In 1891, he injected streptococci into a patient with an inoperable tumor and found that it had shrunk. Subsequent injections led to the complete disappearance of the tumor. Kohli continued his experiments, but was faced with the fact that patients began to die from infection. Then he switched from using live streptococci to bacteria killed by heating.

In total, William Kohli conducted therapy for more than 800 patients, and in more than half of the cases it was successful. This method was used even after the death of its inventor. However, by the 50s - 60s, radiotherapy and chemotherapy of raza were developed, and the "Kolya vaccine" gradually began to lose popularity. In 1963, when, after the thalidomide story, the rules for the registration of medicines in the United States became stricter, the "Kolya vaccine" did not receive automatic FDA approval and its release was discontinued. Several clinical trials conducted in subsequent years have shown contradictory results. Now Kolya's vaccine is produced by small pharmaceutical companies in order to conduct further clinical trials.

The baton was picked up in Japan, where the study of the effect of streptococci on tumors began in the 1960s. In the mid-1970s, the Japanese created the drug picibanil (OK-432) based on specially treated bacteria Streptococcus pyogenes. It has shown significant effectiveness in the treatment of lymphanginoma, a benign tumor of the walls of lymphatic vessels found in children. For the treatment of this tumor, injections of picibanil are still used today.

Kohli himself explained the effect of his vaccine by the fact that bacterial cell toxins in some cases are able to act selectively, primarily inhibiting tumor cells. The current explanation is that the appearance of bacterial antigens activates the body's immune response. Therefore, a number of laboratories around the world are looking for the most effective ways to use bacteria to fight cancer.

Since bacteria often settle on necrotic, oxygen-poor tissues, which are present in most large tumors, scientists can easily target them to tumor tissue. One similar treatment method has already been successfully tested and received approval in the United States from the Food and Drug Administration (FDA). In it, bacteria are used to treat bladder cancer. Several more are under development. But even the most effective of them could not yet exclude the re-growth of the tumor, and the bacteria used were dangerous to the patient's body by themselves. In several cases, the use of weakened salmonella did not bring significant results.

In 2014, a group of American researchers reported on the first results of the use of a weakened strain of soil bacteria and Clostridium novyi in the fight against tumors. In nature, this bacterium multiplies in an oxygen-poor environment, similar in this respect to the conditions in the tumor tissue. Injections of clostridium made it possible to double the life expectancy of rats that had human brain glioma transplanted. The further experiment involved 16 dogs with tumors of different types. In six of them, infection with bacteria caused a decrease in the size of tumors, and in five – their growth stopped. There was even a test conducted on one person – a patient with a severe form of leimiosarcoma, a tumor of the smooth muscles of the peritoneum, which gave numerous metastases. The injection of bacteria was made into a metastatic tumor in the shoulder. The tumor quickly collapsed, however, there were side effects of infection – a strong inflammatory process and the formation of an abscess at the site of bacterial penetration. The patient died, but not because of infection, but because of metastases of leimiosarcoma in other parts of the body.

Work on the therapy method, described in a recent article in the journal Science Translational Medicine (Zheng et al., Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin, began back in 2006, when researchers from Jeongnam University in the South Korean city of Gwangju selected a new bacterium for the role of an assistant in the fight against cancer. At the same time, they were looking for a vaccine against the bacterium Vibrio vulnificus, which infects marine mollusks off the Korean coast. In the course of their work, they noticed that the protein FlaB (flagellin B), which forms the tubules of flagella in this bacterium, causes a particularly strong reaction of immune cells. Then they took a genetically modified bacterium Salmonella typhimurium, which was no longer capable of causing disease in humans, and armed it by inserting a gene responsible for the FlaB protein into its genome.

In the current study, this group of scientists tested the interaction of a modified bacterium with tumors. In the first series of experiments, bacteria were injected into twenty mice that had human colon tumors transplanted. Three days later, scientists discovered that the tumor tissue in the intestines of mice was infected with bacteria. After 120 days, tumors disappeared in 11 of the 20 mice that remained healthy throughout the experiment. Control mice infected with bacteria lacking the FlaB protein eventually developed colon cancer.

In the second experiment, human colon cancer metastasis cells were transplanted into three groups of mice. Eight mice then received salmonella endowed with the FlaB protein, six were infected with bacteria without this protein, and seven did not receive any bacteria at all. After 27 days, dozens of metastases were found in mice of the second and third groups, whereas among the eight mice that got the FlaB protein into their bodies, only four had secondary tumors, and metastasis was very limited.

Scientists explain the effectiveness of the FlaB protein by the fact that it binds to the TLR5 protein (toll-like receptor 5), which plays an important role in the mechanisms of innate immunity. It specifically targets the flagella of bacteria that enter the body, and by binding to them activates the immune response process, acting on immune cells and turning, in the words of scientists, "from Dr. Jekyll to Mr. Hyde."


Now Korean scientists continue to improve their method by experimenting on animals. They expect to switch to human clinical trials in a few years and create an effective and safe method of bacterial cancer therapy.

Portal "Eternal youth" http://vechnayamolodost.ru  13.02.2017

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