02 September 2019

Slow down glioblastoma

Brain cancer can be delayed by immune weapons

Kirill Stasevich, "Science and Life" (nkj.ru ) based on the materials of The Scientist.

Glioblastoma is one of the most frequent and, moreover, the most dangerous brain tumors. According to statistics, after the diagnosis is made, the patient has 6-9 months to live, and even if the tumor was cut out and then a course of therapy was carried out, the disease still returns within seven months. It is extremely difficult to treat it.

Firstly, if we inject some medicine into the blood, then we need to remember that there is a so-called blood-brain barrier in the blood vessels of the brain. The walls of the vessels here are arranged in such a way that they allow only the most necessary things that the brain may need. The barrier protects the brain from everything that can disrupt its physiological harmony, but if there is already some pathology in the brain, then the barrier turns out to be inappropriate - not every medicinal substance can break through it.

Secondly, glioblastoma cells, although they form the same tumor, can be quite different from each other, and then the drug that kills some simply will not work on others. In such cases, immunotherapy is called for help – after all, the immune system must recognize a variety of cancer cells. Immune cells can enter the brain, whose duty is to monitor malignant neoplasms, but glioblastoma, like many other tumors, is able to suppress the activity of the immune system, remaining unnoticed for it.

The activity of the immune system can be spurred with the help of special signals. For example, a patient can be injected with a protein called interleukin-12 (IL-12), which, among other things, stimulates the activity of immune cells that kill cancer. But if you just inject IL-12 into the blood, you can get a lot of strong side effects – "overheated" immunity can even disable completely healthy internal organs.

Researchers from Harvard University, the M. D. Anderson Cancer Center and their colleagues from other scientific centers in the United States acted differently: they used adenoviruses that brought not the IL-12 protein itself, but its gene directly into the tumor. Adenoviruses are "tamed" viruses that do not cause harm, but which are still able to penetrate the cell, bringing DNA into it. 

If the virus is supplied with DNA encoding IL-12, then the cells into which the virus particles have penetrated will begin to produce IL-12 themselves. But it is desirable that they do not synthesize it all the time, so the IL-12 gene was provided with a special "switch": cells began to synthesize an immune signal in the presence of a substance called veledimex, whose molecules are able to penetrate the blood-brain barrier into brain tissue.

In experiments on mice with glioblastoma, the tumor decreased after taking veledimex: it turned on IL-12 in the brain, which awakened the immune system, which, in turn, began to destroy tumor cells. But it wasn't limited to mice. At the next stage, the IL-12 gene in a viral package was injected into the brain tissues surrounding the excised tumor during surgery. Then the patients received different doses of veledimex for several days, which triggered the synthesis of interleukin-12.

The fact that IL-12 was actually synthesized was evident from the level of g-interferon in the blood – another signaling immune protein that reacts to IL-12. The amount of g-interferon increased when veledimex was taken, and decreased when veledimex was stopped, that is, the molecular switch and switch worked as it should. 

Some patients then underwent another operation to remove the growing glioblastoma, and much more immune cells were found in their tumors than in the tumors of patients in whose treatment such a treatment regimen was not used. It was not possible to avoid side effects altogether, but since different doses of veledimex were used in the experiment, it was possible to choose a dose that would allow therapy to be performed without too serious consequences.

However, did all this help the patients themselves? An article in Science Translational Medicine (Chiocca et al., Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial) states that with such experimental therapy, patients lived on average for another 12.7 months after surgery. Among them were slightly more than a quarter of those who lived for 18 months, and another 13.3% of patients lived for two whole years. These figures may not seem very large, but here it should be remembered that with recurrent glioblastoma (that is, when it returns again and again), only 1-2% of patients usually survive until the second year; against the background of these 1-2%, the effect of such therapy is very impressive. It remains to be hoped that the immuno-viral trick with the introduction and inclusion of the immune gene can still be improved so that patients with glioblastoma can live even longer.

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