Nobel Prize in Medicine-2018: immune therapy for cancer or how to make the immune system cope with the tumor itself

The Nobel Prize in Physiology and Medicine in 2018 was awarded for the discovery of a new cancer treatment. Laureates James Ellison and Tasuki Honse explored ways to stimulate the body's immune system to fight the tumor on their own. "Such cases" asked the experts to explain why this discovery was a breakthrough in the treatment of cancer.

Photo: Ye Pingfan / Imago / TASS

Since the 1990s, scientists have been working on two different strategies for correcting breakdowns in the immune system, which prevented it from detecting cancer cells. Both of them can be used for any type of cancer.

Professor Allison discovered a protein in immune T-cells that acts as a brake on the immune system and does not allow it to attack a tumor. He developed an antibody capable of binding to this protein and blocking it. In 2010, Professor Allison conducted an experiment on patients with skin cancer - melanoma, after which some patients disappeared signs of cancer.

Professor Tasuki Honse discovered another protein that also works as a brake on the immune response, but has a different mechanism of action. In 2012, studies have shown the effectiveness of therapy in the treatment of patients with various types of cancer. The results were impressive: up to long-term remission in several patients with metastases in a condition that was previously considered not amenable to treatment.

As commented on during the announcement of the Nobel Prize winners, the novelty of this method of therapy is that the treatment is directed not at the tumor itself, but at stimulating the immune system. Another important aspect of this discovery is that it is aimed at different types of tumors, and not at one.

Vice President of Research and Development BIOCAD

The Nobel Prize has the status of the most prestigious award on the planet. One of the criteria for choosing a laureate is the recognition by the world community of the great importance of its discovery. Over the past three to four years, the results of clinical trials of immunotherapeutic drugs have convincingly shown that immunotherapy is a revolutionary breakthrough in oncology. The presentation of the prize this year for the discovery of the first immunotherapeutic drugs is proof of this.

The discovery of immunotherapy has led not only to a change in the standards of treatment of certain malignant tumors, but, in principle, to a change in the paradigm of treating a patient with cancer. If earlier the main approaches to the treatment of malignant tumors included chemotherapy, supplemented by targeted drugs, surgical treatment and radiation therapy, now we are talking about the emergence of a doctor in the arsenal immunotherapy as the fourth pillar of oncology.

Unlike all other available treatment methods used in the late stages of cancer, in fact only immunotherapy is able to provide long-term remission in a significant proportion of patients. Moreover, in some cases You can talk about the healing of patients with malignant tumors, which was not in principle. That is why immunotherapy is perhaps one of the most significant discoveries in oncology over the past decades.

The mechanism of influence of checkpoint inhibitors on the development of an antitumor immune response has been known for more than 10 years. However, it is only now that the results of numerous clinical studies that confirm the fact of high clinical efficacy and safety of these approaches have become available. The possibilities of immunotherapy were first demonstrated only for patients with melanoma, the proportion of which among all cancers is relatively small.

Now the results of studies in lung cancer, kidney cancer and a number of other common tumors suggest that immunotherapy is not just a way to treat certain groups of patients, but one of the foundations of modern cancer therapy basically. Increasingly, data are being collected on the synergy of immunotherapy with chemotherapy, with radiation therapy. It should be noted that most of the recent studies are devoted to combinations of immunotherapy with chemotherapy: such schemes are the most effective.

In Russia, not so long ago, three foreign immunotherapy drugs were registered and entered the market. Naturally, their use is limited due to the extremely high cost of therapy. Our company has just completed the main stage of a registration study on melanoma, we submit our product to the Ministry of Health for registration, and we hope that in the first half of 2019 it will enter the Russian market and immunotherapy of oncological diseases will become more accessible for patients.

The release of the Russian drug and further competition between various foreign drugs will certainly lead to a reduction in the cost of therapy, but we should not forget that these are high-tech drugs, they by definition cannot be very cheap.

Director of the Cancer Prevention Foundation

I personally deeply believe that if they were given the Nobel Prize, it was for this. I think this principle of treatment will radically change the approaches to cancer treatment in the next 10-20 years. My prediction is that classical chemotherapy will give up its positions and will practically become obsolete in the coming decades, it will be replaced by targeted and immunotherapy. And about anthracyclines and taxanes (anticancer drugs - approx. TD) then there will be children in high schools telling in classes on the history of medicine, and they will scratch their heads and say: “Well, how wild it is, how happy, that we do not live in those times”.

This, of course, is just a wonderful thing - it actually changes the properties of cancer, his biology - in its application, he loses a number of his abilities, which, in fact, allows people with deadly tumors to survive for so long at its use. Miracle, and only. The cool thing is waiting for it to spread to all cancer sites. Melanoma was the obvious target. And here's another forecast (do not ask why I think so) next in line will be bladder cancer and colorectal cancer - I am sure that effective immunotherapy drugs will appear against them soon.

* original of Fomintsev's Facebook comment

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    How does immunity work? T-lymphocytes: helper cells, killers, suppressors

    These cells (helpers, killers and suppressors) belong to T-lymphocytes - this is a type of white blood cells, each of which performs a specific function.
    The main task of immunity is to be able to recognize your own and other people's cells. T-helpers are great at this - they identify a stranger or their damaged cell and stimulate the immune response, causing to work cells T-killers, cells-phagocytes and enhanced antibody synthesis.

    T-killers - this type of T-lymphocytes are key players in protecting the body. They are also called killer cells, cytoxic lymphocytes (“cyto” means “cell”, “toxic” means poisonous). They react aggressively to the presence of defective cells (including cancer) and foreign protein in the body. Let's talk about them a little more.

    With their shoots, they touch the object, and then break contact and leave. Its own “defective” cell or someone else’s cell that the lymphocyte has touched dies after a while.

    The cause of death is the pieces of the membrane left on their surface by the T-killer. Pieces of the membrane cause a through hole in the cell to which they touched, its internal environment begins to communicate directly with the external - the cell barrier is broken. The doomed cell swells up with water, cytoplasm proteins come out of it, the organelles break down ... It dies, and then phagocytes approach it and devour its remnants.

    As you can see, T-killer bodies have receptors that bind to "strangers", label them and force the body to respond to this challenge - to develop protection or to kill invaders. But additional proteins that act as T-lymphocyte enhancers are also needed to trigger a full-scale immune response.

    It T-killers carry out an aggressive immune response with the help of amplifiers - T-helper cells.

    The next group of cells is T-suppressors (“suppression” means “suppression”). If T-helpers enhance the immune response, the suppressors, on the contrary, suppress, regulating the strength of the immune response. This allows the immune system to respond to stimuli with moderate force without causing autoimmune diseases.

    Why do T cells respond to cancer cells of their own, as if they were strangers? The general principle of the interaction of the immune system with tumors is as follows. As a result of mutations in the tumor cells, proteins are formed that differ from the “normal” proteins to which the body has become accustomed. Therefore, T-cells react to them as alien objects.

    This is a very simplified scheme, accessible to the understanding of people without medical education. There are a number of other cells, but these will be enough to understand the task of immunity when detecting "someone else's".

    How a tumor tries to trick the immune system

    A tumor is a system of cells that use a variety of ways to escape the immune system. They learned to "pretend" and "disguise." Some tumor cells hide mutated proteins from their surface, others destroy defective proteins, others secrete substances that inhibit the work of immunity. And the “meaner” the tumor, the less chance the immune system will cope with it.

    Tumor cells have learned to use CTLA4 protein molecules to avoid an attack by the immune system. Cancer cells begin to produce a large number of CTLA4 activators.
    Activators recognize “check points” and thus suppress immunity. Activation of "immunity control points" suppresses the development of the immune response. The CTLA4 protein, which Allison studied for a long time, belongs to such a “control point”.

    The inhibitors proposed by the scientist block these activators and prevent tumor cells from escaping the immune response. The result of the research of the scientist was the development of drugs-antibodies that inhibit "control points" - this is his main discovery.

    Nobel Prize in Medicine 2018: the essence of the discovery

    The Nobel Prize this year is awarded for unlocking T-killer cells. Nobel laureates of 2018 have been helping cancer patients to fight tumors for six years, using the results of their research in practice. Scientists have figured out how a cancer tumor “deceives” the immune system and, based on their research, have created an effective anti-cancer therapy - immunotherapy.

    Among the traditional methods of treating cancer are the most common chemotherapy and radiation therapy. There are also "natural" methods of treatment of malignant tumors, including immunotherapy. One of its promising areas is the use of inhibitors of "immunity control points" located on the surface of lymphocytes (cells of the immune system).

    Both scientists, the winner went to the discovery in different ways. Let's look at what each of them researched and how they managed to get immunity to cope with oncology.

    The discovery of Dr. James Allison

    James Allison was able to unlock the immune system with antibodies against protein-brake. The doctor studied the effect of a certain cellular T-lymphocyte protein (code name CTLA-4). He concluded that this protein inhibits the work of T-killers.

    The scientist was looking for ways to unlock the immune system. He got the idea to develop an antibody that binds the protein-inhibitor and blocks its function of suppressing the immune system. James Allison conducted a series of experiments with mice infected with cancer. He was interested in the question whether protein blockade (CTLA-4) would help antibodies release the immune system to attack cancer cells.

    Cancer Patient Laboratory Mice managed to be cured with antibody therapythat have removed the inhibition of the immune response and unblocked T-lymphocyte antitumor activity.

    In 2010, Dr. Allison conducted clinical studies of patients with melanoma (skin cancer). In some patients, residual traces of skin cancer have completely disappeared - as a result of immunotherapy.

    This is how it looks in the infographics created by the Nobel Committee.

    The immune system will begin to actively destroy "foreign" cells if T-lymphocyte is activated. To activate it you need to contact cell receptor with other immune elements that identify "alien" - antigens. Should now appear cellular immune response enhancerbut it is blocked by CTLA-4 protein. You can unblock it with antibodies against CTLA-4.

    Left Figure shows protein-inhibitor and cellular receptor. The amplifier does not work (green pimples).
    On right - antibodies (green) against CTLA-4 block the function of inhibition of lymphocytes, the inhibitory protein is neutralized by the antibody, the cellular enhancer supplies an enhanced signal to the immune system and T-lymphocytes begin to attack cancer cells.

    The CTLA-4 protein molecule appeared only on activated T-cells. The merit of Ellison is that he suggested that the opposite is true: CTLA-4 appears on activated cells specifically so that they can be stopped.

    That is, on each activated T-cell there is an inhibitory molecule that competes for signal reception (and turning on or off the immunity function). A little higher was considered, how the signal of the “alien” cell T-helper cells is transmitted to the T-killers - and after receiving the signal, the killer cells hit the alien ones. But the CTLA-4 protein molecule intercepts the "alien" signal and blocks the killers.

    The scientist was able to bind with antibodies, an inhibitor protein and release the immune system to attack cancer cells.

    Dr. Tasuku Hongjo discovery

    Dr. Tasuku Honjo a few years earlier also discovered a protein-inhibitor (PD-1) located on the surface of lymphocyte cells.

    Honjo investigated a similar protein in immune cells (PD1) and found out that it works as a brake, inhibiting the development of a tumor and, at the same time, blocking T-killers.

    The scientist also synthesized antibodies to PD-1, which removed the blockage and, as a result, an enhanced immune attack on cancer cells.

    Both blocking molecules, CTLA-4 and PD-1, and their corresponding signaling pathways were called immune checkpoints. checkpoint - check Point).

    Currently, many tests and clinical trials in the field of cancer immunotherapy are being carried out, and new control proteins detected by Nobel laureates are being tested as targets.

    Not less than 15 years passed between discoveries of checkpoints and approval of drugs based on their inhibitors. Now use six of these drugs: one CTLA-4 blocker and five PD-1 blockers. Why were the PD-1 blockers more successful? The fact is that cells of many tumors also carry PD-L1 on their surface in order to block the activity of T-cells. Thus, CTLA-4 activates T-killers in general, and PD-L1 more specifically affects the tumor. And the complications in the case of PD-1 blockers occur somewhat less.
    A source

    What drugs are used for immunotherapy of cancer: name, cost

    In our country, drugs are used for immune therapy of cancer tumors. Most of them are not affordable for ordinary patients.

    In 1995, Allison first discovered T lymphocytes (CTLA-4) that suppress T cells. A year later, a group of researchers led by Ellison developed antibodies that block the activity of T-lymphocytes.
    A new drug has successfully coped with the suppression of certain types of cancer in mice.

    During clinical trials, the survival rate of the subjects was much higher than predicted.

    In 2012, this method was tested on humans: about three hundred people took part in the tests: a third of patients with melanoma recorded a significant decrease in the volume of tumors. Thirty percent of kidney cancer patients also noted improvement.

    Subsequently, the world's largest pharmaceutical companies became interested in the new cancer treatment method. A number of them have developed antibodies that block PD-1 and CTLA-4. One such development, CTLA-4, an antibody for treating metastatic melanoma, has helped nearly a quarter of patients extend their life by three years after diagnosis. This achievement was recognized as a great success.

    Many cancer specialists have noted that although many questions related to cancer immunotherapy still remain unanswered, this is about the birth of a fundamentally new treatment paradigm.
    The prestigious scientific journal Science called the new approach in cancer immunotherapy the main scientific achievement of 2013.

    Unexpected reward

    Elisson is an American cancer immunotherapy specialist, professor at the University of Texas Cancer Center. He has written over 250 articles published in leading scientific journals, and received a number of prestigious awards.

    The American admitted that he had always dreamed of a prize. According to him, the reward came as a surprise to him.

    “I dreamed about it. But I never thought that this would happen. It feels like something big has happened,” said the scientist.

    The award ceremony will be held according to the tradition of December 10, on the day of the death of Alfred Nobel. The sum of each of the Nobel Prizes in 2018 is nine million Swedish crowns (about a million dollars).

    Watch the video: Cancer Basics - Immunotherapy (December 2019).