May the force be with us
Own immunity against cancer
Blog of the company Medicine 24/7, Habr
In recent decades, science has made significant progress in the treatment of cancer, and although we are still quite far from completely defeating this terrible disease, doctors have more and more tools to destroy tumors or limit their growth. The main thing is that they give cancer patients the opportunity to live longer and longer.
One of these tools is the activation of a person's own immunity to fight cancer cells. There is a whole field dedicated to this – immuno-oncology. A lot of attention is focused on it, it is in this area that the most research is being conducted today and the most promising drugs are being developed.
We at Medicine 24/7 actively use immunotherapy – and we see that it gives good results. However, we are faced with the fact that many patients do not know about this method of treatment at all or consider it insufficiently studied and not trustworthy.
In this publication we will try to clarify the issues: what is immunotherapy, how it works and who it can help.
Judy Perkins. She had terminal breast cancer, which was completely cured with the help of the latest immunotherapy method
A hidden threat. How cancer occurs
Cancer cells are mutant rebels who have managed to outwit the system.
In the course of life, all cells of the body go through strictly defined stages of development, perform specified functions, multiply according to strict rules, and eventually age and die. This is a natural process. Programmed death of old cells, in which many breakdowns have accumulated, is called apoptosis.
However, under the influence of heredity or unfavorable external factors, some cells accumulate genetic errors and "rebel": they refuse to live according to the algorithm set by nature, begin to multiply uncontrollably or do not die on time. This is not uncommon. Potentially cancer cells can periodically appear in everyone – this is normal. Almost always, such "upstarts" are killed by the internal security service of the body – immunity.
One of the main roles in this process is played by T-lymphocytes, or, more simply, T cells. They react to an antigen (a substance foreign to the body), recognize and destroy potential enemies: for example, microbes or unsuitable donor material. Normally, T-lymphocytes also kill cells of the body that have begun to mutate and behave not according to the rules. Therefore, cancer does not occur in everyone – in most, the immune system copes with disorders before they spread.
But cancer strives to survive and tumor cells are trying to capture as many resources as possible, to become "more successful". They multiply faster, secrete vascular growth factor (to attract more blood and nutrients to the tumor), develop resistance to drugs, force stem cells to enhance the growth of tumor tissues (by sending deceptive signals with a request for regeneration).
Cancer cells achieve special success in disguise: some of them remove special proteins-antigens from their surface, by which they can be recognized by T cells. Others secrete special molecules that suppress immunity, and some even form hybrids with macrophages (one of the types of immune cells) – and acquire literally superpowers!
In this they are helped, on the one hand, by kinship with normal cells of the body – a kind of innate disguise. On the other hand, the genetic variability of cancer cells gives them increased adaptability. The more mutations have accumulated in the DNA of a cell by the time of its malignancy (transformation into malignant), the more chances it has to survive the immune response and develop a successful capture plan.
The Force Awakens. The history of the Nobel Discoveries
Human immunity is actually a real army of ruthless killers, and after each "combat operation" to neutralize another enemy, they need to be calmed down and transferred from a military to a peaceful situation. This mechanism lowers the temperature to normal values and stops inflammation when the danger has passed and infection is defeated.
The 2018 Nobel Prize in Physiology or Medicine was awarded to American James Ellison and Japanese Tasuku Honjo for their independent discoveries in the same field: how exactly does this switch from aggressive to calm mode happen?
None of the scientists initially thought about cancer treatment. Both of them wanted to understand more clearly the workings of the immune response. By that time, it was clear that both on the surface of T cells and on the surface of antigen-presenting cells (APC) there are receptor molecules that act on each other, provoking or slowing down the immune system. A TCR – T-cell receptor was discovered, by which T-cells recognize "enemy" proteins exposed to APC. The main histocompatibility complex MHC (major histocompatibility complex) was found, with the help of which APC just presents pieces of foreign proteins to T cells for identification. Peter Doherty and Rolf Zinkernagel received their Nobel Prize for the discovery of this scenario in 1996.
Scientists understood that receptors on the surface of T cells work together with co-stimulators on the surface of APC. CD28 protein was isolated from the surface of T cells back in 1980, and soon the B7 molecule was found on the surface of APC. During the experiments, the Ellison group researchers transferred the B7 gene into cancer cells, and they began to be rejected by healthy tissue. It turned out that B7 connects to CD28 on the T-cell, and thereby starts its work: the T-cell destroys the tumor cell, on the surface of which the B7 protein "sticks out".
In 1987, Ellison discovered cytotoxic T-lymphocyte antigen-4 CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) – and found out that this protein is similar in structure to the long–known CD28, and is also able to bind to B7 - however, it acts in exactly the opposite way: it stops the immune response.
CTLA-4 Action
At first, doctors were going to use this "brake" to fight autoimmune diseases (when the immune system begins to attack healthy cells of the body). But Allison came up with a brilliant thing: not to put pressure on the brake, but to turn it off.
He developed an antibody inhibitor (switch) that bound to CTLA-4 and prevented it from closing with B7 to turn off immune responses. The free B7 molecules bound to CD28, the T cell activated and was ready to kill again. When he conducted experiments on cancer-stricken mice in 1995, it became clear that even tricky cancer cells could not hide from such T-lymphocytes with the brakes turned off. In 2010, successful studies were already conducted on hopeless patients. In some patients, melanoma disappeared along with metastases – an incredible result!
Effect of CTLA-4 – ipilimumab inhibitor
At the same time in Kyoto Tasuku Honjo found another receptor molecule on the surface of the T-cell: PD-1 (Programmed cell Death protein-1, Programmed cell Death protein-1). During experiments (again on long–suffering mice), the Japanese found out that disabling the gene encoding this protein provokes symptoms of autoimmune disease in mice - that is, inhibiting PD-1 also turned off the "brakes" in T-lymphocytes and made them aggressive and active.
Honjo found out that PD-1 puts the T-cell into "sleep mode" when it binds to the PD-L1/PD-L2 protein on the surface of the antigen-presenting cell (APC). The PD-1 inhibitor broke this connection and reactivated the T cells. The action of this "brake" was similar to the action of CTLA-4, but took a different route.
Effect of PD-L1 – nivolumab inhibitor
Both discovered "inhibitory" molecules, CTLA-4 and PD-1, were called immune checkpoints – it is their number and activity that make T cells decide whether to calm down or start fighting.
It turned out that CTLA-4 blockers activate immunity in general, all T cells, and the PD-1 inhibitor acts more specifically on tumors, because many cancer cells carry the "second piece of the puzzle", PD-L1/ PD–L2 molecules. Because of this, treatment with PD-1 inhibitors gives a lower risk of complications.
Immunity strikes back. What do checkpoint inhibitors help with?
Ellison and Honjo not only made a serious contribution to the understanding of physiological processes, but also launched a wave of fundamentally new practical research in applied medicine.
The discovery of immune checkpoint inhibition (IICT) opens up a fundamentally new field of search for solutions. The previously existing methods of fighting cancer: surgery, radiation and chemotherapy – were aimed directly at the tumor itself, at the destruction of cancer cells. Now doctors have a huge field for research in a completely different direction: changing the interaction of cancer cells with their environment.
By the way, it was this fundamental difference that gave doctors a real breakthrough. Until now, the tumor has been affected depending on its localization. There is one drug for breast cancer, and a completely different one for stomach cancer. And the ICT inhibitor pembrolizumab in 2017 was registered for the first time in the history of oncology as a drug for the treatment of any cancer in any organ – if only tests confirm that the tumor has a special property: microsatellite instability. That is, her DNA is particularly prone to mutations. Previously, it has never been possible to make a cure for cancer for some common feature. This is a great achievement.
The results of the use of new drugs against the most aggressive types of cancer became a revolution: metastatic melanoma at stage IV was considered incurable. And patients with such a diagnosis who underwent a course of the drug ipilimumab (CTLA-4 blocker) in 2010 received an additional year of life – the development of the tumor was so suspended. In 58% of them, the tumor decreased by a third.
In the treatment of non-small cell lung cancer with nivolumab (PD-1 inhibitor), the risk of death of patients decreased by 40%.
The drug pembrolizumab (also a PD-1 inhibitor) showed a 43% decrease in tumor growth in the group treated for melanoma. 74% of patients lived without deterioration for a year, within 18 months there were 71% of them. It is important that the effect of prescribing the drug outweighed the side effects at all stages of the disease.
Today, CTLA-4 and PD-1 inhibitors are used to treat melanoma (including inoperable), non-small cell lung cancer, squamous cell head and neck cancer, renal cell carcinoma, certain types of lymphomas, rectal cancer, bladder cancer, and tumors with microsatellite instability.
Special attention is drawn to studies that show the effectiveness of combination therapy with both anti-PD-1 and anti-CTLA-4 drugs.
The change in tumor volume is a sharp decrease in the combination of anti–PD-1 and anti-CTLA-4 drugs
Progression–free survival - the combination of anti-PD-1 and anti-CTLA-4 drugs is more effective
In "Medicine 24/7" we have been successfully using pembrolizumab and nivolumab since their registration in the Russian Federation. We followed all the foreign research and were really looking forward to replenishing the arsenal.
Attack of clones. Genetically modified immunity
Immune checkpoint inhibitors are deservedly in the spotlight, but this mechanism is still flawed and cannot cure any cancer. It is good that related research areas are actively developing in immunotherapy. One of the most promising is CAR-T therapy.
The letter T in the name of the method is the same unchanging T–cells of our immunity. CAR (Chimeric antigen receptor) is a chimeric antigen receptor. Why is the receptor called chimeric? Because it is assembled from several parts taken from different cells – with the help of the skills of genetic engineers.
An ordinary T cell has a special TCR receptor (T-cell receptor). He "feels" all the cells of the body on his way and, if he feels some foreign molecule on the surface of the cell, sends an activating signal to the T-cell. She, in turn, either deals with the unwanted alien herself, or secretes special active substances (cytokines) and calls on other immune cells to "sort it out". They kill T cells very effectively.
However, not very accurately. We have far fewer varieties of TCR than there are antigens. Therefore, T cells are able to recognize many antigens with their TCR, but only approximately. Cancer cells often take advantage of this weakness of our security system and pretend to be "their own".
Evolution solved the problem as best it could: there is another mechanism in the human body for detecting outsiders: antibodies. These are special proteins that are secreted by another class of immune cells: B-lymphocytes. B cells, unlike T cells, have an individual approach to each "client".
The antibody is a protein structure in the form of the letter Y. At both ends of this "fork" there are sites that bind to the antigen. These areas can change with each next generation of antibodies in order to fit more tightly to the antigen – like picking up pieces of a puzzle. When a foreign antigen is detected, B cells secrete billions of antibodies, among which there is a selection for the most accurate match to the antigen. As a result, reference antibodies are obtained, "trained" specifically for very accurate recognition of a specific "stranger" – an antigen.
An antibody adapted to find a specific antigen
However, to recognize does not always mean to neutralize. With this, antibodies have difficulties – they can not destroy the "enemy" on their own in all cases.
So, in 1989, Israeli chemist and immunologist Zelig Eskhar came up with the idea to combine the killing power of blind T cells and sniper targeting of antibodies. He isolated the end sections of antibody proteins that are able to bind tightly to the antigen of certain cancer cells, and "transplanted" them into the T cell - replaced them with part of the TCR responsible for antigen recognition.
Subsequently, he began working together with his American colleague, Steven Rosenberg, and they managed to make a chimeric receptor of a more efficient design, both sensitive and selective.
The difference between normal T cells and CAR-T cells
In vitro studies have shown a good result. Then the scientists treated the mice again, then painstakingly transferred the technique to humans.
Over time, CAR-T therapy has been brought to a modern look.
First, with the help of gene-molecular testing, specific mutations in human tumor cells are determined, for which antibodies can be "tuned".
Then, a person's own T-cells are taken from him, modified using bioengineering methods, instead of TCR, "transplanting" a CAR tuned to the identified mutations.
The modified CAR-T cells are then multiplied in a test tube and injected back into the human body, where they successfully recognize and kill cancer cells.
In clinical trials started in 2010, encouraging results were immediately obtained: in the treatment of lymphoma, 12 out of 13 patients showed improvement, and 4 went into remission. In the treatment of leukemia, remission occurred in 17 out of 33 people.
In 2018, an article by American oncologists appeared in Nature Medicine, where it was reported that for two years they have been observing a patient who is completely healthy after CAR-T therapy. She was cured of metastatic breast cancer. This photo of her in a kayak is given at the beginning of the article: after treatment, she returned to work and goes hiking.
A new hope. Will immunotherapy become a panacea?
Like other cancer treatments, immunotherapy has its limitations. Despite the fact that in some cases patients give a very good response to therapy with immune checkpoint inhibitors, in 60% of cases either acquired or primary resistance to anti-PD-1 or anti-CTLA-4 drugs develops: the tumor simply does not respond to treatment or quickly adapts and learns to "bypass it".
In addition to PD-1, PD-L1/2, CTLA-4, CD28 and B7, there are a lot of other co-receptors on the surfaces of T cells and tumor cells, the action of which has not yet been studied as well as the work of control points, but they also affect the immune response. One of the areas of work is the effect on these co-receptors.
In addition, IICT therapy is supplemented with the introduction of vaccines, cytokines, beta-blockers – and this approach also works well in a number of cases.
CAR-T therapy is still extremely expensive and is still only entering the stage of commercial use: developments are underway in the scientific groups of Eskhar and Rosenberg, other researchers – each of the groups creates special types of CAR-T with targeted action against a certain type of cancer. But for now, this is only research, testing and testing. It will take several years before this turns into a proven mass method of treatment – but even then it will be impossible to give 100% guarantees.
But while scientists are conducting research, doctors are introducing experimental treatment regimens using the achievements that already exist. And the most noticeable effect is the combination of immunotherapy with the classic "three pillars" of oncology: radiation and chemotherapy, surgery. When combining these methods, synergy is always obtained: together they work more efficiently than in turn.
If standard immunotherapeutic drugs have been included in the third, fifth line (that is, the queue) of therapy, now doctors are moving to prescribe them immediately, along with chemotherapy and therapy with targeted monoclonal antibodies: such patients often show better dynamics and eventually live longer.
All major immunopreparations have already been registered in Russia. The problem, however, is that the Ministry of Health separately stipulates indications for each of them. That is, in the original instructions for the drug, for example, nine different types of cancer can be prescribed for which the drug can be prescribed, and in our country it is registered only for six of them. And so it is with each drug. As a result, about 50% of tumors have not yet been included in this list. Accordingly, within the framework of CHI treatment, the doctor may prescribe these drugs to far from all patients.
In addition, doctors of state-funded clinics are strictly limited by treatment protocols. And if the control point inhibitors are prescribed in the protocol only on the 3rd line, on the 3rd place after two lines of standard "chemistry", then the doctor simply has no right to prescribe them in the first place, even if he believes that it will help the patient.
Well, a common problem is the lack of qualifications. The method, although it has managed to prove itself, is still new for many doctors in the country. The drugs are all Western, and they reach us 2-3 years late. And, given that immunotherapy has been actively used for only a few years, many still have no experience working with them. In addition, the use of immunotherapy requires specific knowledge.
In private medicine, we are not limited by the budget. If a patient with a tumor for which an immunotherapy drug has not yet been registered applies to Medicine 24/7, we suggest that he undergo a molecular genetic study. According to the results, it becomes clear whether his tumor will respond to the immunopreparation. If yes, the doctor has every right to prescribe it. Therefore, in our hospital we use immunotherapy for almost all types of cancer – it gives very good results. Even patients at stage III-IV show improvements. Immunopreparations give us the opportunity to prolong people's lives, even in cases that were considered hopeless.
The common thing in both private and public clinics is the patients themselves. They do not always understand well what this method is, how it works, hence the distrust. We hope this article helped to understand and understand that immunotherapy today is deservedly in the focus of close attention of oncologists. Judging by the results, it is already ready to get on the same level with classical methods. The terrible disease will recede one step further.
Portal "Eternal youth" http://vechnayamolodost.ru