CAR-T in Siberia
Siberian scientists develop cancer drugs
Progressive Cancer Therapy: CAR-T starts and wins
Elena Klimova, SIBMEDA
Image source: personal archive of A. Gorchakov and S. Kulemzin
Novosibirsk scientists have joined the research of cancer therapy with genetically modified cells of the patient. The results of foreign colleagues are encouraging: from 50 to 90 percent of patients with some types of cancer in the terminal stage go into persistent remission.
Senior researchers of the Institute of Molecular and Cellular Biology SB RAS, PhD Andrey Gorchakov and PhD Sergey Kulemzin tell about the situation with cell therapy of oncological diseases in Russia:
– It is known that cancer cells appear in our body from time to time. However, the own immune system has the ability to recognize and destroy such cells. A person lives and does not suspect what his immune system has protected him from.
But sometimes cancer cells mutate and "pretend" to be healthy, then the immune system does not recognize them. The same can happen with weakened immunity. We are not talking about weakened immunity in the everyday sense, when we say that we easily catch viruses or catch a cold, but that certain parts of the immune system are inactive for various reasons. And then the cancer cells begin to multiply uncontrollably.
If we learn to manipulate the immune system so that it can always identify a cancer cell, then the power of our own immune system will be enough to cure cancerous tumors.
One of the encouraging ways to use the body's capabilities in the fight against cancer, therapy with so-called T–lymphocytes with chimeric antigenic (antigens are substances alien to the body that cause its immune response – ed.) receptors, abbreviated CAR-T, (from the English chemegis antigen receptor T-cell) appeared relatively recently, in the end of the twentieth century.
– And it is called in numerous publications "a breakthrough in the treatment of oncology", "a new era in medicine". Why?
– What is the idea of such a molecule? One of its parts recognizes markers on the surface of the tumor cell, and the other parts transmit an activating signal to the cell of the immune system to destroy the tumor cell. CAR-T cells are produced as follows: T-lymphocytes are extracted from the patient's blood, that is, cells that normally should protect us from cancer and virus-infected cells. Then the DNA encoding CAR is embedded in the chromosomes of T-lymphocytes, and the cell begins to produce on its surface those chimeric, that is, artificially created, non-existent receptors. They are designed so that T-lymphocytes detect markers on the surface of cancer cells and receive a signal to attack them. The CAR T cells obtained in this way are multiplied and injected back into the patient's blood.
– What happens next?
– If the CAR-T in the patient's body collide with a normal cell, then they simply float past each other, if they detect a cancer cell, then the chimeric antigenic receptor recognizes a specific marker on it, to which it was tuned when it was created. The T-lymphocyte kills the cancer cell and begins a very active division. From one cell equipped with a CAR-T receptor, hundreds and even thousands are obtained. Such a self-propagating medicine.
And while there will be cancer cells in some corners of the body, CAR-T lymphocytes will destroy them. When all cancer cells are destroyed, CAR-T lymphocytes will mostly die, some will remain in the bone marrow in order to reappear, multiply and destroy the cancer in case of repeated relapses.
– It sounds convincing. Why, then, even in the best case, the effectiveness of treatment is 50-90 percent, and not 100?
– The tumor is not always homogeneous in composition. For example, 90 percent of cells can carry a target targeted by CAR-T lymphocytes, while 10 percent do not. And these 10 percent remain intact in the body and multiply. In addition, even an initially homogeneous tumor can "escape" from CAR-T lymphocytes if it "removes" or modifies targets on the surface of its cells. There are other problems complicating the treatment with chimeric antigen receptors.
For example, despite the fact that CAR-T cells themselves can live for a long time, in an organism depleted by multiple chemotherapy, they will multiply rather sluggishly and fight cancer cells ineffectively. This is partly why this approach does not work in all cases.
– Is it known what side effects are possible in the treatment of CAR-T cells?
– Clinical trials have already been conducted in the world on several thousand patients with oncohematological diseases, such as acute lymphoblastic leukemia and some variants of leukemia. Side effects are associated with the fact that CAR-T cells are too powerful. Attacking tumor cells, they also affect other cells of the immune system, forcing them to massively release biologically active substances, cytokines, and a condition called a "cytokine storm" occurs. The temperature rises, the pressure drops to critical values, hallucinations are possible, the kidneys may fail. This condition requires resuscitation.
It is gratifying that doctors have already learned to predict and control the development of a cytokine storm in most patients. In addition, let's not forget that the risks associated with CAR-T therapy are generally lower than with bone marrow transplantation used in patients with leukemia as the last line of therapy.
– For which types of oncology is CAR-T therapy effective today?
– Initially, therapy was used for acute lymphoblastic leukemia, the type of cancer that children most often suffer from. Perhaps that is why there is information about the greatest effectiveness of CAR-T therapy for the treatment of children. But in adults with this disease, the result was no worse.
Now this therapy shows an effectiveness of 50-90 percent in the treatment of patients even with end-stage lymphoblastic leukemia, lymphoma and myeloma.
There are attempts to treat so-called solid tumors with CAR–T cells (Solid tumors are a collective designation of tumors that have a certain localization – location, and this differs from another group – tumor diseases of hematopoietic and lymphoid tissue – leukemia – ed.), but it is not yet possible to achieve a satisfactory result.
- why?
– The fact is that it is quite difficult for a CAR-T cell to penetrate into such a tumor, it is necessary to move against the pressure gradient, in a solid tumor, CAR-T cells literally have nothing to breathe. And cancer cells also actively defend themselves and secrete substances that can kill or "put to sleep" a CAR-T cell. It turns out that CAR-T cells, even those that have reached the tumor, are not able to perform their functions. Solid cancers are very common.
And now hundreds of companies around the world are conducting their own clinical trials to adapt this technology for the treatment of solid types of cancer. Technological solutions are being created in order to force the cell to migrate into the tumor, survive in an aggressive environment, and attract additional cells of the immune system to help itself. Preclinical studies on mice show convincing results. Clinical (on patients) are still modest.
But considering that the whole world is doing this now, very serious clinics, pharmaceutical companies and universities, we are confident that in the near future different types of cancer will become more susceptible to CAR-T therapy.
– At the expense of what?
– You can choose other carrier cells, and our laboratory is also involved in these developments. Or modify the host cell itself, change its genome, so that its properties then change. We are thinking of doing this as well. So far, we are modifying the CAR so that they stimulate the lymphocytes not too much, but not too weakly either. So that the lymphocyte is not stimulated in the absence of a cancer cell, so that rare markers are better found on the surface of cancer cells. We are engaged in the creation and modification of CAR for markers of acute lymphoblastic leukemia and prostate cancer. In the latter case, we cannot yet talk about the clinical result, the work is being carried out on mice.
– What are the prospects for the use of chimeric antigenic receptors for the treatment of oncological diseases in our country?
– Pay attention to the schedule of distribution of clinical trials by countries of the world (Graph 1).
Schedule 1. Image source: A. Gorchakov, S. Kulemzin
According to the total number of clinical trials conducted, China is in 3rd place. According to CAR-T therapy – on the first! (graph 2).
Schedule 2. Image source: A. Gorchakov, S. Kulemzin
And this is despite the fact that fundamental scientific work in the CAR-T field is mainly conducted in the USA. What is the reason for this? Due to the fact that in China the legislative policy regarding the conduct of clinical trials is the most loyal, they have practically turned clinical trials into a therapeutic process. Chinese scientists use CAR-T developed in laboratories around the world, analyze other people's experience, conduct clinical trials, and at the same time develop their own CAR-T products. And the flow of cancer patients from different countries, including Russia, seeking CART-cell therapy in China, is becoming more and more.
– And what is happening in this area in Russia now?
– In Russia, thanks to the energy and enthusiasm of doctors, one clinical trial of CAR-T cells is being conducted at the Center for Pediatric Hematology named after. Dima Rogachev.
– Against 160 in China? What prevents them from repeating their experience?
– Yes, the Chinese way of developing CAR-T therapy looks the most acceptable for Russia. If we follow the path of creating our own CAR-T receptors from scratch, then we are waiting for interesting, but very long studies, and patients can be helped right now.
The difficulty is that the existing Federal Law "On Biomedical cell products" of 23.06.2016 N 180-FZ (ed. of 03.08.2018) has not been finalized. In the version in which it exists now, the introduction of CAR T-cell products into practice requires procedures similar to the introduction of chemicals.
Even for preclinical CAR tests, T cells must be produced in GMP (Good Manufacturing Practice) format, the tests themselves must be carried out by GLP (Good Laboratory Practice) - certified laboratories. This effectively cuts off academic science from the development of CAR T-cell therapy. Now scientists are hoping for by-laws that will soften the existing requirements.
Cell therapy is a new tool of medicine, and a new, balanced regulatory approach should be developed to it. In the meantime, we receive letters with questions about where and how you can undergo CAR-T therapy. And we answer: "In China."
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