Modified lymphocytes against blood cancer
How to help the immune system
Alexandra Bruter, <url>
From December 6 to December 9, the annual meeting of the American Hematology Society was held in San Francisco. A lot of attention was paid to the use of modified lymphocytes for the treatment of lymphomas and leukemias.
In order for a malignant tumor to form and grow in the body, several events must occur sequentially. The cells of multicellular organisms have mechanisms that prevent the cell from dividing when it is not necessary. In order for tumor growth to begin, these mechanisms must break down. When the mechanism breaks down, the cell has ways to feel it and commit suicide, but this does not always happen. Uncontrolled growth alone is not enough to cause a tumor to appear, since the body has the next line of defense. Usually, the immune system recognizes cells that have become malignant and kills them. Therefore, no one will ever know about most of the regenerated cells. But some cells, in addition to the ability to multiply uncontrollably, get a superpower – to deceive the cells of the immune system. That's why life-threatening tumors grow out of them, which the body itself can no longer cope with.
So if the immune system can cope with some regenerated cells by itself, maybe it can be helped a little, and then it will cope with some others? This concept has been developing in recent years in several directions at once.
The first of these areas, which will be discussed in this note, are the so–called CAR (chimaeric antigen receptor, chimeric antigen receptor) T cells. The cells of the immune system are not able to look inside other cells of the body, they only see what is on the surface of the cells. In turn, the cells of the body have a mechanism by which intracellular proteins sometimes appear on the surface so that they can be inspected by cells of the immune system. This is useful, for example, for antiviral immunity. The virus has entered the cell – it is not visible to the immune system. But as soon as it begins to synthesize its proteins, some of them are on the surface, the immune system recognizes the cell as infected and kills it. This mechanism has been refined in order to treat proliferative blood diseases. On the surface of almost all B-lymphocytes there is a molecule called CD19. It is absent on the surface of T-lymphocytes and all other cells. To combat B-cell diseases, scientists have created T-lymphocytes, which, in addition to the usual antigenic receptors for recognizing, for example, virus-infected cells, had an artificially created chimeric antigenic receptor that recognizes the CD19 molecule. We wrote about the methodology in detail and about the first, extremely optimistic, test results earlier.
Clinical trials of the method began in 2007. Then the researchers could not find anyone willing to participate – their idea seemed so unexpected. But the therapy, which proved itself well in experiments with animals, was intended for people who had nothing to lose – the standard arsenal of modern medicine could not cope with the disease, people had only a few months to live. The results of three clinical trials were presented at the conference. In the first, six patients recovered from lymphoma. In the second of 23 patients with chronic leukemia, 9 improved. In the third of 30 patients with acute leukemia, 27 recovered. These are all very optimistic results, given that these people were basically doomed. They also inspired optimism in the hearts of investors from pharmaceutical companies. At least five large and several small pharmaceutical companies have invested significant amounts in the development of the technology. Kite Pharma invested $ 127.5 million in the project, Juno Therapeutics – 310 million. Companies hope, of course, to make a profit. The technology is very expensive, according to preliminary estimates, the cost of treating one patient can be about half a million dollars. It is calculated that 10 billion people will be cured in a year. Americans, of course, will not have to pay for therapy out of their own pocket, but the technology will hardly reach Russia. Perhaps charitable foundations will be able to send some children abroad.
In fairness, it should be noted that therapy has dangerous side effects. When the immune system deals with viruses in the body, a person feels sick: his temperature rises, there are pains in muscles and joints. At the molecular level, these symptoms are caused by inflammatory mediators produced by activated lymphocytes – for example, interleukins. Since the same phenomenon occurs during CAR-T-cell therapy, and quite violently, many inflammatory mediators are released into the blood at once. Several patients died from an excessive immune response, the research had to be stopped and the methods revised. Research using new methods turned out to be less risky.
Lymphomas are convenient for such a therapeutic approach because malignant cells are easily accessible to engineered lymphocytes, and they have the same molecules on their surface that allow them to kill selectively. This is not true for other types of tumors. But this does not mean that immunotherapy cannot be adapted to them.
We have already said that at one of the levels of the body's defense against tumors, the immune system recognizes mutant proteins presented on the cell surface that provide the tumor with its malignant properties. In theory, there may be infinitely many such mutations, but in practice a small number of mutations are responsible for a large percentage of tumors. Two research groups have compiled a catalog of such mutant proteins and learned how to create personalized vaccines based on them – so far, however, only for mice.
The cells of the immune system are able to recognize a tumor cell by the mutant proteins presented on the surface, but they lack the strength to cope with it. Recombinant mutant proteins can help. Vaccination against infectious diseases works according to this principle. The human immune system is able to learn: when it encounters an infection for the first time, it still has nothing to oppose the disease. In a few days, the immune system picks up antibodies to pathogens (if the patient does not die) and the disease wins. This doesn't always work. But sometimes, based on this principle, diseases can be prevented. The immune system is introduced to the safe form of the pathogen (sometimes only with fragments of its outer shell), it remembers it (sometimes for a lifetime, sometimes for a couple of years) and meets it fully armed.
Even when it comes to rapidly occurring infectious diseases, vaccination is not always necessary to carry out in advance. In Louis Pasteur's experiments, even a few Russians bitten by rabid animals were saved, although they were bitten in Russia, and vaccinated in Paris, and no one flew by planes. Oncological diseases proceed more slowly, and it turned out that if a dose of mutant protein was injected into mice that already had tumors, the tumor was rejected and the mice recovered.
Another promising area of research is devoted to preventing tumors from hiding from the cells of the immune system. Some tumors are able to produce PD-L1 protein, a ligand of the PD-1 receptor located on the surface of lymphocytes. Ordinary cells of the body use this protein and this receptor to transfer lymphocytes to a resting state and avoid autoimmune reactions. Inhibition of this system in patients in some cases contributes to recovery.
Portal "Eternal youth" http://vechnayamolodost.ru16.12.2014