A new era in oncology

Wake up, immunity!

Galina Kostina, "Expert" No. 47-2013

At the ESMO European Oncology Congress, discoveries and developments in the field of immunotherapy were called a new era in oncology. However, targeted therapy, which became a revolution 15 years ago, also continues to develop rapidly.

The forecasts of experts presented at the ESMO Congress are shocking: every second of the current newborns is a potential cancer patient. This is a tough challenge for scientists and developers of new drugs for the treatment of oncology. Scientists admit that they are still far from fully understanding the nature of cancer. However, the powerful forces thrown into the study of tumor biology are yielding results. The evolution of the fight against cancer is happening before our eyes. The first anticancer drugs appeared almost in the middle of the last century. These substances hit all rapidly dividing cells, which, in addition to cancer cells, also include epithelial cells, hair follicle cells, some blood cells, and were far from safe for the body. Doctors complained that patients often die not from cancer itself, but from the toxic effects of drugs. Already in the late 1980s, a new class of drugs began to be developed - the so–called targeted drugs that acted selectively on a specific target in a tumor cell. These new drugs, which began to appear in clinics since the late 1990s, gave reason for optimism: doctors began to say that the formula "cancer is incurable" is a thing of the past. Some types of cancer turned out to be curable, others began to succumb to therapy – the survival rate of patients began to increase. Scientists and doctors call the new era developments aimed at activating the immune system, originally designed to fight all foreign or altered cells.

Chemistry of cellular dialogue

Oncoimmunology is older than chemotherapy. Back in the XIX century, doctors noticed that some cancer patients, when infected with an infection - erysipelas or rabies – developed a powerful immune response that acted on the tumor. From time to time, they returned to this topic, in the laboratories they tried to direct immune cells to tumor cells, but the researchers did not receive encouraging results. Chemotherapy was also included in the force, radiotherapy methods were rapidly developing, surgery was improving – they gave up on immunity.

"In recent years, there has been a significant evolution in the study of cancer biology and immunology. It has already been precisely established that mutations are constantly accumulating in the cells of the body, which are monitored by control systems. The accumulation of a critical mass of mutations can lead to the appearance of a tumor," says Irina Baldueva, a leading researcher at the N. N. Petrov Research Institute of Oncology. – The processes of the origin of a tumor cell or mutation are reflected on its surface: proteins appear on it – the so-called antigens. They are like signal flags telling the environment: attention, the cell has changed. And the cells of the immune system immediately recognize these antigens, go to the altered cells and deal with them." It is not yet known at what point and why this balance between the emerging abnormal cells and the immune system is disrupted. According to Irina Baldueva, the stage of "evasion of tumor cells from immune surveillance" begins. Until recently, there was no complete clarity at all about the relationship between cancer and immunity. Only recently have scientists begun to better understand the complex interaction between different cells, including cancer cells and cells of the immune system.

"The cells are in a constant dialogue," says Marina Granovskaya, Manager for Scientific Cooperation at Roche. – Imagine a tumor where there are not only cancer cells in a dense clot, but also different cells of the immune system that still see something and strive for tumor cells. There are also sprouted vessels. There are also a lot of signaling molecules – cytokines, which are constantly releasing both tumor and immunocompetent cells. Actually, these signaling molecules are the chemistry of the intercellular dialogue." It is not so easy to understand this variety of molecules. There may be more than 50 different types of antigen proteins on the surface of a cancer cell (and these are only the detected ones!) All the signaling molecules that the cancer cell secretes for different purposes, mainly protective ones, have not yet been studied. The cells of the immune system themselves are not fully understood: what proteins sit on them, what their functions are, what substances these cells emit into space. This tangle of tumors lives its own life, cells and signaling substances change all the time, like topics of conversation. At some point, tumor cells can remove antigens from their surface so that the immune system does not see them. Or they send signaling substances that block the receptors of immune cells, as if they close their eyes or deprive them of their activity. The immune system doesn't seem to give up either. For example, it activates part of its "sleeping" cells.

Researchers are trying to understand this tangle, to hear "intercellular conversations", to see proteins that are important for the functions of both tumor cells and immunity. One of the discoveries was the beginning of the history of a new product that can become a hope for many cancer patients. "Ten years ago, scientists engaged in HIV research discovered one of the mechanisms by which a virus–infected cell is masked," says Marina Granovskaya. – The virus attacks the cells of the immune system, and it is depleted as a result of a powerful response to infection. The affected cell exposes on its surface the antigen protein PDL–1, designed to bind to the immune cell receptor. When a cell of the immune system gets close to a virus-infected cell, this protein binds to its receptor and thereby seems to disarm it. Scientists researching cancer, seeing this message, thought that a similar mechanism may be in tumor cells. And indeed, we found that tumor cells also have such a protective protein on their surface."

Zombified security

"For almost thirty years, we have not understood why a tumor disarms the immune system," says Daniel Chen, head of the global development group for a new molecule from the American company Genentech, part of the Roche group. – The discovery of new proteins on tumor cells and on cancer-attacking T-lymphocytes allowed us to see sophisticated cancer methods. I will try to compare this situation with the control system at the airport. Imagine that you pass the control when boarding the plane, and the security guards scan you: if you are okay, you are allowed to pass, if not, you are detained and taken away. This is how the immune system works as a security. However, it not only takes away a stranger, but also destroys him. What do we observe in the tumor? Security seems to see a suspicious type, but, like a zombie, it becomes numb and can't do anything, and the suspicious type bypasses control and goes on. It turns out that a suspicious type is a tumor cell that throws a PDL–1 protein onto its surface, and when a security T-lymphocyte approaches it in order to see and destroy it, this protein connects to a receptor on the T-lymphocyte. The tumor protein seems to stretch out its arms and stops the T-lymphocyte. Moreover, two T-lymphocyte receptors are blocked at once – PD-1 and B7 (see diagram. – “Expert"). So the immune cell loses not only the ability to recognize the tumor, but also its murderous activity." As soon as the scientific idea was developed, Genentech began to search for a substance that would interfere with this coupling, preventing the immune system from recognizing and attacking the tumor. The research started about 10 years ago.

According to Daniel Chen, even at Genentech itself, many people were skeptical about this project: they say they fought for decades trying to make the immune system work against the tumor, and everything ended in collapse. But that's the strength of this world's first biotech company, that it has always given its scientists and developers freedom, giving them the opportunity to go their own way, even if some project seemed hopeless to others. "Our new anti-PDL-1 molecule, which was supposed to block this coupling, was not believed even when we approached the stage of clinical research," Chen continues, "But when we saw the first results in just a few patients, skepticism disappeared, and the company was seized with a real drive."

Daniel, telling the story of one of these patients, is not shy about his emotions. In February 2011, Jeff Schwartz was fatally diagnosed with late-stage kidney cancer. This is one of those types of cancer that is practically untreatable at all, let alone in the late stages. The tumor was not only in the kidneys, it metastasized to the lungs, heart and other organs. The condition deteriorated rapidly, Jeff did not get out of bed anymore. His lawyer friend, having learned that the doctors were giving Jeff Schwartz only six months of life, said on one of his visits: I'm sorry, friend, but it's time for you to do some paperwork and settle all your affairs. Jeff's two little daughters didn't understand what was going on with Dad and why he stopped playing with them and generally living a normal life. Dad is sick, they were told. It was hard to prepare for the worst, there was not the slightest hope. This painful condition was disturbed by the message of Jeff's attending physician: the study of a completely new drug is beginning, let's try it.

"I was fantastically lucky," Jeff later said. And the head of those clinical trials , Mark Willigan , commented: "I was also happy to see Jeff recovering before my eyes after anti-PDL-1 therapy. Not only did he get out of bed, after a few months he returned to his business and even started attending a sports club!"

Jean-Charles Soria, a professor at a Paris university and the head of early clinical programs for new drugs, was one of those who distrusted this development. But the first clinical studies made a huge impression on him: "It's one thing when you hear about some theoretical research, and quite another when you see that it works, as if a switch is flicking in the body." Professor Soria talks about the good results that have been obtained in the treatment of patients with lung cancer. According to him, combination therapy can give an even greater effect (such studies are currently underway): a special targeted drug allows you to reduce the tumor, and anti-PDL-1, turning on the immune system, helps to destroy it or minimize it.

Both developers and clinicians, not to mention patients, have high hopes for this drug: it is quite versatile. In principle, the drug can act on many types of cancer and be the magic bullet that doctors and patients dream of. According to Daniel Chen, the company hopes that the inspiring results will allow it to undergo accelerated clinical trials. In this case, the drug can be registered in three years.

At the ESMO European Oncology Congress in Amsterdam in October, the message about anti-PDL-1 aroused great interest among oncologists. By the way, there were a lot of reports on developments in oncoimmunology. According to Daniel Chen, now many biotech and large pharmaceutical companies are conducting similar developments. They are associated not only with the PDL-1 protein, but also with other proteins sitting on the surface of both tumor and immune cells, as well as with signaling substances that trigger these cells. Genentech also has such projects. "The more new drugs appear in this area, the easier it will be for clinicians to select the necessary funds for certain tumors," says Chen.

Make way for vaccines

Twenty years ago, the first reports appeared in the press about the development of therapeutic vaccines for oncology. More than a hundred vaccines are currently being studied in many laboratories around the world. Relatively recently, only two have been registered: vaccines for prostate cancer provenge and for renal cell carcinoma - oncophagus. The latter will be produced under an agreement with the American Agenus by a young Russian company "NewVak" ("daughter" of "HimRara"). NewVak is also conducting research on combinations of this vaccine with additional substances. "The task of the vaccine is to provide the immune system with information about the tumor antigen, the task of an additional molecule – the so–called co-adjuvant – is to break through gaps in the protection of the tumor from immunity, and this protection is quite diverse," says Andrey Golubev, medical director of the NewVak company. The co-adjuvant just hits one of the signaling molecules of the tumor, which prevents the T-lymphocyte from attacking this tumor (we wrote about this development, see the article "Double blow to cancer" published in No. 14 of the "Expert" for 2012). According to Golubev, this is an absolutely new word in modern oncology, the adjuvant should significantly increase the duration and improve the quality of life of patients.

Vaccines aimed at activating immunity are being developed in several Russian institutes: the N. N. Blokhin Russian Cancer Research Center, the P. A. Herzen Moscow Research Institute of Oncology, and the N. N. Petrov Research Institute of Oncology in St. Petersburg. In the latter, in particular, several vaccines have been created, one of which has already been registered and is used for treatment. "We have been developing vaccines since 1985," says Irina Baldueva. – And they all work on the principle of activating the immune system against the tumor. We apply vaccines to patients who are already practically insensitive to any other therapy. And we see that vaccines work, and they are most effective in a widespread process." The only registered vaccine is already being used to treat tumors such as melanoma and soft tissue sarcoma. Baldueva explains that the drug can be applied to those tumors that have foci on the surface of the body. Photosensitizers are injected into the affected focus, which accumulate in all dividing cells. The cells of the surface focus under the influence of a photosensitizer become sensitive to laser irradiation. Laser irradiation puts these cells into a state of programmed death – apoptosis. And in a state of apoptosis, they are recognized by the immune system, whose forces will be thrown at their destruction. "However, in order to affect the cells that are not only in the superficial focus, but also inside the body, we introduce a vaccine with dendritic cells," says Irina Baldueva. The action of these cells of the immune system in the body can be represented as follows: when they meet with a foreign agent or a tumor cell, they capture their antigens and expose these antigens to themselves as the brightest flags that will attract other cells of the immune system. So, after laser irradiation at the Petrov Research Institute, a large dose of dendritic cells that are not yet "trained" (without flag antigens) is injected, which load themselves with antigens already in the patient's body and migrate to the lymph nodes to encourage T-lymphocytes to fight tumor cells throughout the body.

"In our other developments, we try to load dendritic cells with different antigens presented by the tumor, hoping to cause an even more pronounced and powerful response of the immune system. Unfortunately, not all tumor antigens are known to science yet, but over time there will be more and more of this knowledge and they will be used in development," Irina Baldueva continues. "Even more unfortunately, even those vaccines that we have already created and conducted clinical trials with cannot enter into widespread practice, since there is no appropriate legislative framework for their use in the country." As everything is fundamentally new, these technologies are difficult to bring to registration according to existing laws that do not keep up with innovations. It was possible to register only one vaccine, and then due to the fact that some temporary regulatory documents were in effect. Now everyone is waiting for the adoption of the law on cellular technologies, although experts call it far from perfect. In particular, in the draft of this law, according to Baldueva, vaccines are not mentioned at all. Nevertheless, oncology is an area where the expectations of patients and doctors are extremely high, so they are looking forward to new developments. And the possibilities of their application.

Survival Molecules

Hopes for oncoimmunotherapy do not mean a weakening of research in the field of targeted drugs, because they have led to significant progress in the treatment of various types of cancer in the last 15 years. At the congress in Amsterdam, the results of the use of many such drugs and reports on promising developments were discussed.

"A lot of cancers are curable if the cancer is detected in the early stages and remains localized," says Evgeny Imyanitov, head of the Department of Tumor Growth Biology at the N. N. Petrov Research Institute of Oncology. – Over the past two decades, we have seen huge progress in relation to breast cancer, cervical cancer, melanoma, not only due to the appearance of new drugs, but also due to elementary attention to oneself. In developed countries, mortality from cervical cancer has almost disappeared, because many women undergo an examination every year, from breast cancer – because women over fifty participate in screening, from melanoma – people just examine their skin. The improvement of diagnostics, the emergence of modern methods continue to bear fruit, the situation in oncology is improving. But, of course, a huge role is played by new targeted drugs that have appeared in the last 15 years and are already helping patients, and new developments that give great hope."

Targeted drugs selectively target certain targets in a cancer cell and, unlike traditional chemotherapy, do not have a negative effect on healthy cells. They are developed by both large companies – Roche, Novartis, Astra Zeneca, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Bayer, Takeda, Boehringer Ingelheim and others, as well as small biotech companies. "Among the first targeted drugs was trastuzumab – against one of the forms of breast cancer," says Lyudmila Manziuk, head of the department for the study of new antitumor drugs at the N. N. Blokhin Russian Research Center. – New knowledge in tumor biology allows an increasing number of targeted drugs to appear. In particular, so-called antiangiogenic drugs have been developed."

For decades, the process of vascular neoplasm has been the subject of interest of scientists developing new antitumor drugs.

Currently, more than ten drugs that affect angiogenesis have already entered clinical practice; dozens more molecules are in different phases of clinical development that will help improve the results of treatment of many types of common solid tumors in the future. One of the first such drugs was bevacizumab. It is used against breast cancer, ovarian cancer, non-small cell lung cancer and colorectal cancer in combination with other drugs that can act on specific tumor targets. Such a drug as aflibercept also has an angiogenic effect. It is approved for colorectal cancer therapy.

Thanks to modern scientific achievements, progress has been made in the treatment of common forms of lung cancer – a disease previously considered fatal. "With the advent of targeted drugs in the field of lung cancer therapy, a lot has changed," says Alexey Gurochkin, head of the medical department at Boehringer Ingelheim in Russia. – This year, a second-generation drug, afatinib, has been added to the treatment of common non-small cell lung cancer. Afatinib differs fundamentally from the first-generation drugs in that it affects all vascular growth factor receptors and significantly improves the results of treatment of patients with non-small cell lung cancer who have not previously received antitumor treatment. There is also experimental evidence that afatinib is active against drug-resistant lung cancer. Another drug of the company – nintedanib – acts against three types of receptors at once. We hope it will soon become available for the treatment of advanced lung cancer. The company is actively conducting clinical developments to improve the treatment of lung cancer, colorectal cancer, malignant tumors of the head and neck, glioblastoma, and other malignant neoplasms and hopes to achieve some progress in the treatment of patients in the future."

Drugs aimed at inhibiting the so–called kinases - about 1000 molecules involved in the transmission of signals in tumor cells - can be quite universal. There are some that are involved in signaling pathways in many types of cancer. In particular, a new drug sorafenib is already being used for two indications – liver cancer and kidney cancer. "Six months ago, the results of a study of sorafenib for thyroid cancer were published, another clinical trial is underway for breast cancer," says Dmitry Vlasov, head of the development of the medical department of Bayer. "If they are successful, the drug will be registered and patients will receive a unique medicine in their class."

Oncologists call imatinib one of the most successful kinase inhibitors. "Its appearance has led to the fact that a huge number of people with chronic myeloid leukemia are really cured. In general, this disease has simply ceased to be fatal, patients live with it as with diabetes mellitus or another chronic disease, lead almost a normal lifestyle, – says Evgeny Imyanitov. – Two years ago, no one would have thought that one of the most terrible skin diseases – malignant melanoma would be treated with medicines. But there are drugs that have great effectiveness." The first in 2011 was vemurafenib, which blocks one of the main signaling molecules in this mechanism. "The doctors observed a very quick response to therapy, the tumors resolved literally before our eyes," says Milos Petrovich, head of the Roche representative office in Russia. – But the medicine did not become a panacea, there was a group of patients who were insensitive to it. Therefore, the company is actively developing a new drug that combines combined effects on several targets at once."

More recently, another drug has appeared – ipilimubab, which in some cases cures melanoma. It is known for activating the patient's immune system against the tumor. Both doctors and patients have high hopes for medicines of this completely new class, because in the future they can become quite universal for many types of cancer.

"We can talk about a number of areas in which patient survival has significantly improved," continues Evgeny Imyanitov. "In particular, patients with colon tumors who were previously allowed six to eight months, now live six to seven times longer."

Despite the fact that significant progress has been made in the treatment of some types of cancer, there were groups of patients suffering from the same types of oncology with certain mutations in genes that did not respond even to innovative drugs. And these groups were also targeted by developers. In particular, the drug iressa has become a very effective tool in the fight against common non-small cell lung cancer with a mutation of one of the genes. Another example: Hodgkin's lymphoma. In general, it responds well to treatment, but there are patients who are resistant to existing types of treatment. They are mostly young people, and they die quickly. The new drug brentuximab vedotin gives them hope. It affects a relatively recently discovered protein, which is mainly present on tumor cells of Hodgkin's lymphoma. Clinical studies have shown the high efficacy of this drug.

According to Evgeny Imyanitov, there are still types of cancer that are still poorly treatable. There are problems with pancreatic cancer, very slow progress is observed in relation to stomach cancer, esophagus, liver, sarcomas. Scientists and pharmaceutical companies are now paying special attention to these areas, trying to find specific "keys" to them, as well as force the patient's immune system to fight the tumor.

There are medicines, there is no money

The draft federal budget of the Russian Federation for 2014-2016, prepared by the Ministry of Finance, assumes a reduction in healthcare costs by almost 34%. Stagnation in the economy, increased defense spending and the implementation of ambitious infrastructure projects such as the Moscow–Kazan high-speed road or grandiose sporting events (for example, the 2018 FIFA World Cup) are cited as reasons.

Dmitry Borisov, executive director of the leading Russian public anti-cancer organization "Equal Right to Life", deputy chairman of the Association of Oncologists of Russia, like many oncologists of the country, fears that cutting the budget for healthcare will put the lives of cancer patients in question. "Together with the Center for Social Economics, we conducted a study that showed that out of almost three million cancer patients, more than a million may find themselves in a difficult situation in two months: they will be forced to buy the necessary expensive medicines at their own expense," says Dmitry Borisov. – At the same time, all responsibility for the health of patients in conditions of radical underfunding will fall on doctors. We are told: those funds for drug provision that the federal budget does not provide will be compensated by the regions. But it is already becoming obvious that many subjects of the federation simply will not be able to allocate the appropriate money. Even in such surplus regions as the Republic of Tatarstan or the Kemerovo Region, there is a serious underfunding of drug provision for cancer patients."

The designers of the "budget maneuver" propose to focus on the implementation of the insurance principle of financing healthcare. But even the initial analysis, according to the experts of the Center for Social Economics, shows that the plans for the growth of tax revenues to the budget of the FOMS are unrealistic. The way out of the situation may be an increase in federal funding and the introduction of a mechanism for co–financing treatment through voluntary insurance - the main tool for protecting the population from financial risk at the time of receiving medical care.

Experts note that over the past 15 years there has been a significant breakthrough in the field of cancer treatment in the country. Now more than half of the patients are recovering – and this is the merit of innovative drug therapy. "However, in the conditions of the "budget maneuver", even the most talented doctor will not be able to help patients," Dmitry Borisov notes. – The planned "budget maneuver" is an attempt to save money on what it is impossible to save on – on the health of citizens and future generations."

Portal "Eternal youth" http://vechnayamolodost.ru 25.11.2013