Cancer Immunotherapy: Nobel Prize In Medicine

2024 Author: Josephine Shorter | [email protected]. Last modified: 2023-12-16 21:43

Cancer Immunotherapy: Nobel Prize in Medicine 2018

In medicine, there is a major breakthrough in the treatment of cancer. In the past few years, the results of clinical studies have been published. All of them ended in a complete victory over malignant neoplasms.

Every year 600,000 people are diagnosed with cancer in Russia. Moreover, 50% of them die from the disease. In the first year after the detection of a pathology, death occurs in 22% of people. All over the world this figure is much lower.

Much is known from cancer, but very little is known at the same time. This paradox leads to the fact that people continue to die of disease. A special problem is presented by advanced forms of oncology, in which tumors metastasize. It is difficult to cope with such a pathology. The most favorable prognosis for those patients in whom cancer is diagnosed in the early stages of development. Nevertheless, significant breakthroughs have been achieved in the treatment of certain types of oncology.

Content:

• Background: what is cancer?
• 2018 Nobel Prize in Medicine: what is the essence of the discovery
• The principle of the method
• What drugs are used for cancer immunotherapy
• Method Risk Assessment
• CAR-T cancer gene immunotherapy
• What is the essence of this treatment?
• CAR T-cell therapy regimen
• Registered drugs for CAR-T
• Side effects of CAR T therapy
• What has been the success in CAR-T cancer gene immunotherapy?
• What else are scientists working on

Background: what is cancer?

Cancer is a malignant tumor that contains mutated cells. They divide and grow rapidly, affecting nearby tissues. At a certain period, the tumor begins to spread its metastases throughout the body.

Tumor neoplasms can develop from various cells of the human body: from the dermis, bones, muscles, nerve fibers. Therefore, neoplasms grow in different parts of the body. The more doctors know about the location of the tumor and the structure of its cells, the higher the chances of successfully getting rid of the neoplasm. Specialists are able to draw up the optimal treatment regimen. Despite this, it remained a mystery why some tumors cause rapid death of the patient, others respond well to therapy, and still others appear again after a few years.

Cancer is not controlled by the body. Her cells have their own DNA. They know how to disguise themselves in such a way that the immune system does not see them.

Methods for the treatment of cancerous tumors that are used in practice:

• Operation. It is designed to remove the primary focus of tumor and metastases, to save a person from complications that were caused by a growing neoplasm.
• Chemotherapy. Treatment is aimed at reducing the size of the tumor, at removing metastases. With its help, it is possible to reduce the risk of recurrence of the pathology.
• Radiation therapy. This therapeutic method affects the tumor at the local level, which allows you to suppress the growth of the neoplasm.
• Hormone therapy. It is indicated for patients who suffer from breast cancer or prostate cancer.

The main disadvantage of chemotherapy and radiation therapy is that not only atypical, but also healthy cells are affected during treatment. The skin, mucous membranes and bone marrow are affected. It is in the latter organ that blood cells are formed. Therefore, patients undergoing chemotherapy develop a host of side effects. They are diagnosed with anemia, they begin to suffer from intestinal problems, their hair falls out. Even with the use of the most modern drugs and techniques, doctors are unable to protect healthy cells in the body.

2018 Nobel Prize in Medicine: what is the essence of the discovery

The Nobel Prize in Medicine and Physiology was awarded in Stockholm on October 1, 2018. Two scientists received it at once - this is the American James Ellison and the Japanese Tasuku Honjo. The award was presented for their research in the field of cancer treatment.

Immunologist James P. Allison, Professor of the Cancer Center and. Monroe Anderson University of Texas, member of the US National Academy of Sciences and US National Academy of Medicine. The scientist is now 70 years old.

Immunologist Tasuku Honjo. He is a professor at Kyoto University, where he has been teaching since 1984. The scientist is a member of the US National Academy of Sciences, the German Academy of Naturalists "Leopoldina" and the Japanese Academy of Sciences.

The merit of scientists lies in the development of an innovative approach to cancer treatment. Their method is different from chemotherapy and radiation therapy used all over the world. The name of the method is Immune checkpoint therapy. It is a cancer immunotherapy that can reduce the activity of abnormal cells and prevent the destruction of the immune system. Application of this method forces the immune system to actively attack the cells of the neoplasm ^[1].

Scientists have discovered the ability of the body to suppress the activity of T-lymphocytes. These immune cells are responsible for killing cancerous tumors. If you block the mechanisms of suppression of T-killers, then the lymphocytes are "released" and begin to independently eliminate tumor neoplasms.

The principle of the method

The human immune system is made up of many cells. If we consider it globally, then the body's defense is represented by activators (stimulants) and inhibitors (inhibition process). When these two systems balance each other's work, a person's health is excellent. Immunity is able to cope with any disease on its own.

T-lymphocytes are white blood cells that are represented by suppressors, killers, and helper cells. Each type of cell is responsible for a specific function. T-helpers must recognize their own and foreign cells. When abnormal cells are found, they stimulate the immune system to work harder. T-killers and phagocytes begin to arrive at the problem area, and the process of antibody production is activated in parallel.

Killer T cells are the most important cells in the body's defense. Scientists call them killer cells or cytotoxic lymphocytes ("cyto" - a cell, "toxic" - poisonous "). They react to all foreign or defective cells and proteins in the body. Cancer tumors are represented by just such cells.

T-suppressors are responsible for suppressing immune processes in the body. They prevent the immune system from being overly active. This avoids the development of autoimmune diseases.

When a tumor begins to grow in the body, proteins are formed in it, which have an atypical structure. They are different from those proteins that the body is used to. T cells react to them as if they were foreign objects.

The tumor, in an effort to maintain its own vitality, tries to deceive the immune system. Cancer cells have the ability to disguise themselves. They remove defective proteins from their surface, or destroy them. Tumors are even capable of producing special substances that reduce the activity of the human immune system. The more active the neoplasm, the less the immunity has a chance to cope with it.

Discovery by James Ellison. This scientist found a way to unblock the immune system by using antibodies to get rid of the inhibitor protein. The doctor studied the functions of the cellular protein of T-lymphocytes (he was given the name CTLA-4). He managed to establish that it is he who blocks the work of the T-killers. The scientist was trying to find a way to unblock immunity. In the course of his research, the doctor decided to create an antibody that can bind the inhibitor protein and interfere with its work.

The experiments were carried out on rodents with cancer. The scientist was trying to find out whether blocking CTLA-4 would help activate the immune system and make it work against tumor neoplasms ^[2].

Ellison's main merit is that he was the first to put forward a version of the relatively "unhealthy" appearance of CTLA-4 on T-killers. That is, this protein is formed on immune cells so that the tumor can stop them. Each active killer T cell has an inhibitory molecule that competes with other molecules for receiving a signal from the immune system (signals can be of two types: turning on and off the body's defenses). If CTLA-4 is located on the surface of the T-killer, then it intercepts the signals coming from the T-helpers and the immune system does not direct its efforts to fight cancer.

In 2010, the scientist conducted tests no longer with rodents, but with people suffering from skin cancer (melanoma). In some of his patients, after immunotherapy, residual traces of this aggressive type of cancer completely disappeared.

Discovery of Dr. Tasuku Honjo. In 1992, this Japanese scientist identified the PD-1 protein molecule on the surface of T-lymphocytes. This abbreviation stands for Programm cell death protein 1, which translated from English means "protein of programmed cell death." The scientist found that it works as a brake. Protein not only inhibits the growth of neoplasms, but also blocks T-killers ^[3].

Tasuku Honjo synthesized antibodies to PD-1, which allowed to eliminate the existing blockage and increase the activity of the immune system against cancer cells.

Antibodies against PD-1 are effective in the treatment of melanoma, non-small cell lung cancer, renal carcinoma, Hodgkin's lymphoma and more.

PD-1 and CTLA-4 and their signaling pathways have been called immune checkpoints by scientists. They were able to show how cancerous tumors can be dealt with by destroying the elements that hold back the immune system.

More than 15 years have passed since the opening. During this time, preparations were developed and introduced into practice that contain inhibitors of immune checkpoints. Cancer is treated with 1 CTLA-4 blocking drug and five PD-1 blocking drugs. This difference in the amount of created agents is explained by the fact that many tumors also have PD-1 on their surface. Therefore, PD-1 blocker drugs allow targeting the tumor, while CTLA-4 blockers affect only the activity of T-killers. In addition, there are fewer complications from the use of PD-1 blockers.

What drugs are used for cancer immunotherapy?

The first clinical trial of drugs was carried out in 2006 on people with cancer. It involved a remedy called Nivolumbus. This drug is a PD-1 blocker. However, it was approved for the treatment of cancer patients only in 2014. At the same time, all tests of the drug Pembrolizumab, produced by Merck, were completed.

In Russia, such drugs have passed registration:

• Pembrolizumab (Keytruda). It is used to treat lung cancer and melanoma ^[4]. Its undoubted advantage is its high efficiency in the treatment of metastatic malignant tumors. The price of one bottle is 3290 euros.
• Opdivo (Nivolumab). This drug is analogous to Keytruda, but it costs less. It is successfully used to treat kidney cancer and melanoma. The cost of the drug is $ 915 for a 40 mg package and $ 2200 for a 100 mg package. Depending on the supplier and manufacturer of the drug, the price for it may differ.
• Ervoy (Ipilimumab). The drug is prescribed for adults and children over 12 years of age at a dosage of 3 mg / kg. A full treatment course will require 4 doses. Enter it within 1 hour 30 minutes. The procedure is carried out once every 21 days. The cost of one bottle with a dosage of 50 mg / 10 ml: 4200-4500 euros, and with a dosage of 200 mg / 40 ml - 15,000 euros.
• Tecentrik (atezolizumab). This drug is prescribed for the treatment of urothelial and non-small cell lung cancer. The price of the drug depends on the intermediaries and the place of purchase. In the USA, 1 bottle costs $ 6500-8000.

These drugs are used both as independent units and in various combinations. This treatment is indicated for patients with inoperable metastatic melanoma, Hodgkin's lymphoma, recurrent and metastatic squamous cell carcinoma of the neck and head, and inoperable bladder cancer.

Immunological preparations for the treatment of cancerous tumors are also produced in Russia. It should be understood that the practical application of checkpoint therapy has just begun. Naturally, in a few years there will be much more drugs in this group. With their help, it will be possible to treat other types of cancer. The cost of therapy will be more affordable, since most of the costs have been left behind.

Method Risk Assessment

Immunotherapy should not be taken as a panacea for cancer. The use of these drugs does not guarantee 100% recovery of the patient. Medicines do not work on all types of cancers. The genotype of a particular patient matters.

Treatment with immunologic drugs carries the risk of side effects. They mainly come down to the development of autoimmune reactions. Since the main active ingredients affect the human immune system, activating it, it begins to work too actively. Therefore, the patient often has autoimmune inflammation of the internal organs.

Another disadvantage of these drugs is that they can be used to treat adults. They are not prescribed for small patients.

It is forbidden to prescribe immunological drugs to pregnant women, as this will lead to fetal death. The fact is that a child inside the mother's womb uses the same mechanisms of escape from immunity as cancerous tumors.

In some patients, these drugs do not work at all, since tumor cells show special maneuverability and hide from the attacks of the strengthened immune system.

CAR-T cancer gene immunotherapy

CAT-T is an innovative cancer treatment that was presented by the American Society of Clinical Oncology (ASCO) in the report "Advances in Clinical Oncology 2018" ^[5].

The therapy is based on the ability of T-lymphocytes to fight chimeric antigen receptors. This treatment is called CAR-T (chimeric antigen receptor T-cell) for short.

Zelig Eshkhar of the Weizmann Institute of Science in Rehovot, Israel, first thought about creating chimeric antigenic receptors for CARs. A chemist and immunologist by training, he was the first to obtain transgenic T-lymphocytes containing CAR. The discovery was made in his laboratory.

However, clinical studies of this new cancer treatment were not completed until 2017. In the course of their implementation, 2 medicines Kymriah and Yescarta were created and approved for use.

If we consider CAR-T globally, then it can be attributed to several treatment methods at once: to gene, cellular and immunotherapy.

What is the essence of this treatment?

CAR technology allows you to set a new program for the patient's immune cells outside his body. Scientists are creating CAR T cells that have the ability to find cancerous tumors and destroy them. The resulting CAR cells are used for adoptive immunotherapy (adaptive is one of the varieties in cancer treatment).

CAR T cells are obtained using ex vivo technology, that is, from human blood. T-lymphocytes are isolated from it, which are responsible for protecting the body from cancer and other pathological cells. Then DNA encoding CAR is inserted into the chromosome of the T-cell. Thanks to such changes, T-lymphocytes begin to produce chimeric receptors on their surface. They allow T cells to find markers located on the surface of cancerous tumors. Once they are detected, a signal is sent to the immune system to attack. CAR T cells are multiplied outside the human body, after which they are injected into the patient's blood.

If a genetically modified cell meets a normal healthy cell, then it does not respond to it. When a cancer cell is detected, the chimeric antigen receptor "sees" on it a marker for which it was previously programmed. The T-lymphocyte sprays onto the tumor cell and destroys it, after which it begins to actively divide. This allows you to completely get rid of cancer.

T-lymphocytes, which are introduced into the patient's body, have the ability to increase their number. Therefore, scientists refer the resulting drug to "live". Initially, only a few altered T cells enter the bloodstream. When a cancerous tumor is detected, these cells are actively dividing, turning into a whole army.

Until all of the tumor cells are destroyed, the CAR lymphocytes will not stop working. When there are no cancer cells left in the body, most of them will die. However, a small supply will still remain in the bone marrow. If there is a relapse of the disease, then they will begin to divide again to resist cancer.

This method is suitable for the treatment of such types of tumors as:

• Aggressive B-cell lymphoma.
• Acute lymphoblastic leukemia in children and adults.
• Large B-cell lymphoma. It is possible with this method to get rid of diffuse lymphoma.

Now scientists are conducting research aimed at combating other types of tumors using the CAR method.

CAR T-cell therapy regimen

CART refers to an innovative cancer treatment that was developed in America. Already, the world's leading oncological clinics have worked out this treatment regimen. Its implementation in practice is considered safe and reliable.

Figure - methods of cell therapy ex vivo and in vivo:

To begin with, the patient will need to undergo a series of diagnostic procedures. If there are no contraindications to CART, then the patient is prescribed treatment. It lasts for several weeks. During this period, the person will be either in the hospital or at home.

1. First stage: blood sampling. Doctors use special equipment to take the patient's blood. It is divided by isolating leukocytes. This procedure is called leukapheresis. It takes about 5 hours to donate blood.

2. Second stage: processing of T-lymphocytes. Blood cells undergo genetic modification under laboratory conditions. Scientists induce the expression of chimeric antigenic receptors that will seek out and eliminate tumor cells. At this time, a person can be outside the hospital walls.

3. The third stage: chemotherapy before the implementation of CART. The person will need to be tested again before the treated T cells are injected. Sometimes it happens that further treatment with this method is no longer possible. If nothing has changed, then the patient is prescribed chemotherapy for a short period. During this period, tests will need to be taken every day.

4. The fourth stage: the introduction of T-lymphocytes. Their infusion takes about half an hour, although sometimes the procedure can take up to 1 hour and 30 minutes. Then, for about 5-6 hours, the person should remain under medical supervision. If there is a risk of side effects, the patient is left in the hospital for several days.

The FDA requires follow-up of patients who have completed CARTs for at least 15 years.

Registered drugs for CAR-T

In 2017, 2 drugs were approved that are suitable for CART. They were approved by the Food and Drug Administration (FDA) based on clinical trials.

Kymriah (tisagenlecleucel). This is the first drug produced by Novartis. They began to use it en masse on 2017-30-08. Treatment can be carried out in children and adults under 25 years of age diagnosed with advanced blood cancer ^[6].

Kymriah is prescribed for patients who have failed to achieve positive dynamics in the treatment of blood cancer with conservative methods and with the help of bone marrow transplantation. Recurrence of pathology is not a contraindication to therapy.

Its high cost does not allow the introduction of the drug Kymriah for mass use. It will take $ 475,000 to create gene T cells and inject them into a patient. The cost is indicated without taking into account the payment for hospital services.

Although the drug is already available for use, scientists continue to study its properties. The drug is now at the stage of post-marketing observational studies.

Yescarta (axicabtagene ciloeucel). This is the second drug that can be used to implement CAR T-cell therapy. It began to be used from 2017-18-10. It is produced by Kite Pharma Inc.

Treatment with this drug is given to patients with large B-cell lymphoma in adults, provided that the disease does not respond to other therapies and recurs. The only contraindication is primary lesion of the brain or spinal cord with lymphoma ^[7].

The price for this drug is extremely high at $ 373,000. Drug manufacturers are actively looking for ways to reduce the cost of the process of its creation. This will make the drug available to more people.

Side effects of CAR T therapy

The implementation of the CAR T-therapy method allows the cells of the immune system to detect the tumor and destroy it. However, the activation of immunity cannot pass without leaving a trace for the body. Patients often have severe side effects.

In order to be able to carry out CAR T therapy, medical institutions must have a special certificate. Doctors are obliged to inform the patient about the health consequences that arise after the treatment. It is important to assess all possible risks.

Side effects develop 1-22 days after the introduction of the altered cells.

These include:

• Weakening of the immune system, a sharp decrease in the level of leukocytes in the blood, the development of infections.
• Anemia, hypotension.
• Acute renal failure. This complication is uncommon.
• Nervous system disorders. Sometimes cerebral edema may develop.

The most common adverse reaction is the so-called cytokine storm. It develops in 75% of patients. Cytokines are proteins that control immune function. After the meeting of the altered T cells with the tumor, a huge amount of cytokines is released into the blood. This reaction is accompanied by an increase in body temperature, vomiting, diarrhea, and increased weakness. If you cannot cope with this condition for a long time, the likelihood of death increases.

In order to prevent a massive release of cytokines into the blood, the use of blockers is recommended.

In order to prevent the development of a cytokine storm, the patient is prescribed the drug Actemra (Tocilizumab) or classic NSAIDs, for example, Diclofenac.

What has been the success in CAR-T cancer gene immunotherapy?

On November 30, the results of the annual implementation of gene therapy in practice were summed up. The customer was the United States Food and Drug Administration. It was this organization that gave permission for the use of medicines. The results were published in the New England Journal of Medicine. 93 patients were treated ^[8].

It was found that 37 patients managed to completely get rid of the disease. Another 11 people began to feel much better, but they failed to achieve a complete victory over cancer. Therefore, the scientists concluded that the technique works by 50%.

Situation in Russia

For the first time in Russia, CART technology was implemented at the N. N. Dmitry Rogachev (NMITs DGOI). The head of the long-term work is the doctor of medical sciences Mikhail Maschan. At the initial stage, the project was supported by the Grant Life Foundation. The possibility of implementing the method within the walls of this medical institution appeared thanks to donations from the top management of Rosneft and the Doctors, Innovation, Science for Children fund.

In 2018, 20 children and young people with acute lymphoblastic leukemia and B-cell lymphomas received treatment. Other therapeutic methods have failed to achieve recovery. The only hope remained for CART.

In Russia, this treatment is required every year for several dozen children and several hundred adults. Mikhail Maschan.

What else are scientists working on

In 2018, there have been tremendous advances in cancer treatment. New breakthroughs are expected in 2019.

Cancer immunotherapy

In addition to the CFR-described T-cell therapy, tumor-infiltrating lymphocyte (TIL) therapy is under development. This method has already eliminated metastatic breast cancer in a 49-year-old female patient. However, large clinical trials have not yet been conducted ^[9].

Liquid biopsy: an accurate and easy test for cancer

A liquid biopsy can help diagnose cancer with a blood test. New tests provide an opportunity to monitor the treatment process and anticipate possible relapse.

Recently, there have been many tests from various companies that assure the effectiveness of their products. However, in 2018, the American Society of Clinical Oncology (ASCO) stated that most of these products cannot be used to detect and monitor disease. This is due to the lack of proven effectiveness of these tests ^[10].

Reducing the side effects of treatment

If in the past decades the main efforts were made to find effective ways to fight cancer, then in 2018, studies were carried out aimed at reducing the side effects of treatment. This primarily concerns male infertility and impaired puberty in girls after chemotherapy. Enough attention was paid to preventing cosmetic defects in appearance that occur after removal of the breast, etc.

Oncological diseases and microflora of the body

Scientific articles have appeared that indicate that the microflora is able to predict the body's response to chemotherapy ^[11].

A publication in the journal Nature Communications ^[12] indicates that certain bacteria present in the human microbiome are capable of affecting the state of the human immune system and causing the growth of multiple melanoma (blood cancer that cannot be treated). It is possible that the destruction of the detected bacteria will influence the treatment of cancer.

Organelles

Organoids are miniature organs artificially grown in a laboratory from a person's own cells that can transform cancer. Information about this appeared in the media back in 2017. Organoids can be used to test various drugs and predict what reaction the patient's body will give to treatment.

These technologies have been adopted by many large organizations. Organoids are supplied to various laboratories, thanks to which it has already been possible to increase the efficiency of the ongoing work on the screening of anticancer drugs.

Organoids are not an ideal environment for drug testing. These mini-organs are not supplied with blood and have no connection with other body systems. However, scientists continue to improve organelles and how they are grown. They will be used much more actively in the future.

Video: Professor Daniel Chen (USA) at the conference "Immuno-Oncology" (April 6, 2018, Moscow) "Cancer immunotherapy: from theoretical foundations to breakthroughs in treatment":

Article author: Mochalov Pavel Alexandrovich | d. m. n. therapist

Education: Moscow Medical Institute. IM Sechenov, specialty - "General Medicine" in 1991, in 1993 "Occupational Diseases", in 1996 "Therapy".