Leukemia gene therapy: the development of success

Maxim Rousseau, Polit.roo

Scientists from the USA continue to improve the method of combined gene-cell therapy of leukemia, the first clinical trials of which began in 2010. Since then, gene therapy has allowed a number of patients to get rid of the disease, whose condition was previously considered hopeless. Recently, specialists from the Fred Hutchinson Cancer Research Center in Seattle reported success in treating another group of patients.

Recall that this method is designed to combat chronic lymphocytic leukemia and acute lymphoblastic leukemia. With both of these diseases, the number of B-lymphocytes in the body increases (with lymphoblastic leukemia – in their immature form, lymphoblasts). These are some of the most common types of blood cancer.

Scientists from the University of Pennsylvania decided to “train” the cells of the immune system to attack the patient's B-lymphocytes, thereby ridding him of leukemia. At the same time, however, healthy B lymphocytes are destroyed, but their absence can be compensated by giving the patient immunoglobulins in the form of injections.

T-lymphocytes were trained. Their main task is to destroy damaged cells of the body, in particular tumor cells. In order for T-lymphocytes to learn to recognize and attack B-lymphocytes, they need to be equipped with a receptor, a special protein on the cell membrane that responds to a specific target. Scientists have created such a receptor artificially from fragments of protein molecules. The target for him was the CD19 receptor, which is located on the surface of B-lymphocytes. But the created receptor must also be placed on T-lymphocytes. To do this, it was necessary to deliver a gene into their genome that triggers the production of the necessary protein.

As a result, the process looked like this. Blood samples were taken from patients. T-lymphocytes were isolated from this blood. These T-lymphocytes were endowed with the necessary gene using a specially modified virus. As a result, a receptor protein that recognizes the CD19 receptor of B lymphocytes appeared on their surface. Then the genetically modified T-lymphocytes were sent back to the patient's body, where they began to fight against atypical B-lymphocytes that cause lymphocytic leukemia.

It is worth clarifying that the fight of T-lymphocytes with the enemy occurs in two ways. Having found the target, T-lymphocytes divide, forming two types of cells. First, some cells directly go on the attack, releasing cytokines – signaling substances that activate other cells of the immune system that can kill foreign cells. Secondly, other cells that have arisen as a result of division ("memory cells") remain in the body for life and, upon subsequent penetration of their opponent, reactivate the immune defense. Therefore, once we train T-lymphocytes, we get a permanent guard ready to destroy the pathogen (in this case, the B–lymphocyte).

Treatment is difficult for patients. When T-lymphocytes are activated and release cytokines into the blood, a condition similar to the announcement of a general alarm on a ship occurs in the body – a nonspecific immune response. The temperature rises, fever occurs, blood pressure may drop sharply and even pulmonary edema may develop. This very life-threatening condition is known as a "cytokine storm".

But in the end, the therapy was effective. In the first clinical trial, which lasted from 2011 to 2013, four patients went into complete remission and eventually returned to normal life, only taking medications periodically to compensate for the absence of B-lymphocytes in the body. Therapy partially helped four of them, and it was ineffective for three more. This is a very good indicator, given that the trials involved patients who were not helped by either chemotherapy or bone marrow transplantation. Among the cured patients was the famous girl Emily Whitehead.

A year and a half later, doctors from Pennsylvania reported the results of a new clinical trial in which 30 patients had already participated. This time, 27 people went into remission. Again, we must remember that this method of therapy was used in very severe cases of the disease, when standard methods of treatment did not help.

But problems persisted. In some patients, after remission, the trained T-lymphocytes soon disappeared, so the disease returned. Many patients also had a "cytokine storm", because of which they had to resort to urgent resuscitation.

Now, specialists from the Fred Hutchinson Center have reported on a new clinical trial of gene therapy for leukemia. The head of the laboratory Stanley Riddell reported on their work at the annual conference of the American Association for the Advancement of Science in Washington in February this year (Engineering T Cells for Safe and Effective Cancer Immunotherapy).

This clinical trial was launched in May 2013. It was attended by patients not only with acute lymphoblastic leukemia, but also those who were diagnosed with non-Hodgkin's lymphoma. Some of the participants had about several months to live, as their disease was recurrent and resistant to other treatments. At the moment, 27 out of 29 participants with acute lymphoblastic leukemia have sustained remission. For non-Hodgkin's lymphoma, complete or partial disappearance of the tumor was observed in 19 out of 30 people.

Riddell and his colleagues also proposed a way to mitigate the "cytokine storm". They were able to reduce the dose of modified T-lymphocytes injected into the body, which reduced the production of cytokines and eased the condition of patients in the first days after the start of therapy. After the optimal dose was selected, the scientists report, they did not need to place any patients in the intensive care unit, saving them from the cytokine storm. With the same dose of T-lymphocytes, seven people were admitted to the intensive care unit.

Now scientists are working both on further improving the effectiveness of the method and its safety for patients, and on the possible use of gene therapy for the treatment of other cancers, in particular breast cancer and some types of lung cancer.

Portal "Eternal youth" http://vechnayamolodost.ru  11.04.2016