Complex therapy in oncology

Galina Kostina, "Expert Online" 

Our journal wrote two years ago that encouraging results were obtained during clinical trials of a drug for cancer immunotherapy (see "Wake up, immunity", No. 43 for 2013). At the recent European Cancer Congress held in Vienna at the end of September, the topic of immune therapy in oncology was the main one. Several drugs have already entered the market, several more are in the last stages of research, and there are hundreds of developments in the portfolios of pharmaceutical companies. Companies focused on the topic of immunotherapy in oncology are significantly expanding their divisions, since even the creation of a single drug designed to activate immunity against a tumor gives a fan of possibilities for its combination with existing drugs, including chemotherapy or targeted drugs. The conditional diagram, which oncologists willingly demonstrated at the congress (see Graph 1), allows us to imagine how new methods of combating tumors can bring patients to a plateau called "life".

Loss of balance

Usually, a small number of degenerated cells constantly appear in the human body. Since they are "wrong", the immune system, designed to keep order, recognizes them and destroys them. But at some point, the healthy equilibrium state is disturbed. Perhaps the last "fly in the ointment" was added to the mutations accumulated in the cell, and uncontrolled growth began. Until recently, scientists did not understand very well what was happening, why and in what situations the immune system stopped fighting tumor cells.

But the fact that it can effectively fight was known at the end of the XIX century. In an American hospital, surgeon William Kohli encountered a case where a patient was cured of cancer after falling ill with an erysipelas infection. And Koli began to collect evidence of such cases. Seeing that the infection could somehow overcome cancer, in 1891 he ventured to inject live streptococcal bacteria to a thirty-year-old Italian with the last stage of inoperable bone sarcoma. The patient went on the mend. The next two patients also had shrunk tumors, but they died from the infection itself. Having modified his vaccine so that it would not infect patients, Kohli in 1893 began to administer it to patients with bone sarcomas. In 1935, he reported on the brilliant results of the five-year survival rate of patients with inoperable forms of cancer. His patients lived. And his vaccine was called "Kolya toxins".

Not everyone was enthusiastic about Kohl's toxins, besides, in the middle of the century, the rapid development of other cancer treatments – chemo and radiation therapy - began. Despite the efforts of Kolya's daughter, who tried to revive interest in her father's methods, scientists and doctors were keen on other areas of research, which then seemed much more promising.

Now many people regret that for many years the direction of immunotherapy was practically forgotten, because if it had developed more intensively, perhaps we would have already had more impressive results in the fight against cancer. However, the fact that this area began to develop actively in the XXI century also gives a serious reason for optimism. Of course, for more than a hundred years, scientists have received a huge amount of information that now allows them to know more about what is happening to cells, how they conduct a "dialogue" with each other. "Of course, we don't know everything about the nature of cancer and the subtleties of the immune system," says Dr. Roy Baines, senior vice president of Clinical Development at MSD (Merck & Co. in the USA and Canada), "But gradually discovering new details, we try to use them as quickly as possible first for development, and then for the treatment of cancer patients."

More recently, scientists, according to the head of the group for development in the field of cancer immunotherapy at Genentech (a division of Roche), Daniel Chen, did not understand why tumors could avoid attacks by the immune system. This understanding began to appear only fifteen years ago in connection with HIV infection research. It turned out that the cell affected by the virus exposes an antigen protein on its surface, which, when meeting with a cell of the immune system, binds to it and blocks its activity. The antigen protein was named PD-L1. And the news was extremely interesting to oncologists: maybe the cancer cell disarms the immune cell in the same way? And, indeed, studies have shown that the tumor cell acts in the same way: it exposes the PD-L1 antigen on its surface. If we imagine that this is the hand of a tumor cell, then it grabs the arm (it was called PD-1) of an immune cell – a T-lymphocyte and thereby triggers a signal about the termination of the immune cell's fighting intentions.

Untie the lymphocyte hands

These first results have become a very good driver for the start of the development of new drugs. Now pharmacologists have a target, or application point. Now these application points are called checkpoints. It became clear that it was necessary to prevent the "handshake" of PD-L1 and PD-1, and this can be done with the help of antibodies blocking these proteins (see diagram). Then the T-lymphocyte, whose hands will no longer be tied, can freely engage in its function: the release of active substances that destroy the tumor cell. Pharmaceutical companies have started developing such antibodies. The lesson is not fast: it is known that it takes from ten to fifteen years from an idea to a medicine.

Daniel Chen, a scientist, developer and oncologist in one person, two years ago told about the amazing cases of the effect of a drug that is at the stage of clinical trials. As a doctor, he understands especially well what it is like for a patient with a metastatic form of cancer: after all, he has almost come to terms with the imminent departure. But hope comes to life when he is offered to try a completely new remedy. And he comes to life himself after several injections of the drug. Genentech has developed not just an antibody to the tumor protein-the PD-L1 antigen, it has been made so that it does not interfere with the work of other cells and is as gentle as possible for the body. Daniel Chen noted that the drug is almost ready for registration, which should take place in early 2016. "A few years ago, we tried approaches to only two types of cancer – melanoma and lung cancer," says Chen, "and now we are conducting research on very many types of cancer. And we are incredibly pleased that many patients whom we treated with our atezolizumab in the framework of research live for three to four years, although they, patients with widespread metastases, had only months left."

Genentech is not the only company targeting this checkpoint. An antibody to block PD-L1 is also being developed at AstraZeneca. Now the drug of this company durvalumab is in the third phase of clinical trials, that is, it is also about to be ready for registration. MSD and Bristol-Myers Squibb have created antibodies against another molecule, PD–1, located on the surface of the T-lymphocyte, and these drugs also prevent the disarming power of the tumor cell. Professor of the National Taiwan Medical University and head of the oncology department of the University Hospital, Dr. Chun Hsiu, is very impressed with the effect of using the drug pembrolizumab: "My research concerned the so-called nasopharyngeal cancer, common in our country. The patients had cancer in severe form, they did not receive chemotherapy for the first time, but the cancer progressed after that anyway. Usually in such cases, the patient remains a maximum of ten to eleven months with the disease continuing to develop and a terrible condition. Therapy with an immune drug has interrupted the progression of the disease for eight months so far, but research continues. It is very important for us to see that hopeless patients continue to live."

Four large companies seem to be participating in a competitive race. "In fact, it's inspiring, because there are so many types of cancer and companies are researching drugs in many directions. Patients with melanoma or lung cancer, kidney or bladder cancer and other types of research get a unique chance, and the developers themselves expand the range of use of drugs," says Daniel Chen. In addition, the more similar drugs appear on the market, the more patients will be able to get them, the faster the prices for them will be leveled, comments Roy Baines from MSD.

Fan offensive

Oncologists have already called the development of the first antibodies for immune therapy a revolution. However, now they pin even more hopes on the development of new drugs that act on other application points, and combinations of immune drugs with other methods. "If we look at the immune cycle, we will see how many opportunities open up for influencing the activation of the immune system against a tumor," says Daniel O'Day, head of the pharmaceutical division of Roche. "Today we are developing more than twenty drugs that affect various checkpoints of the immunotherapy cycle. Seven of them are already at the stage of clinical trials."

The immune cycle begins when one of the guardians of the immune system, the dendritic cell, approaches the tumor. It "reads" information from the protein-antigen of the tumor and drags this news to the center of the army of the immune system – to the lymph nodes. There, the dendritic cell can transmit this information by training and encouraging T-lymphocytes to tumor antigens. T-lymphocytes are sent through the bloodstream to the tumor and seep into its environment (see diagram). All along this path, the points that can be affected have already been marked. "For example, we aimed at the stage that occurs in the lymph nodes. We are developing an antibody to one of the receptors on the T-lymphocyte in order to further activate it to fight the tumor," says Daniel Chen.

AstraZeneca is also working on the same application point called OX40. Here, at the stage of late clinical trials, there is another new molecule – an antibody to another T-lymphocyte receptor – CTLA-4. At normal times, a signal passes through this receptor that inhibits the activity of the immune cell. This is a physiological mechanism, since any immune response must be stopped at some point. The company is investigating a combination of two antibodies – durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4). The fact is that taking only the first drug in the form of monotherapy is very effective in treating about 25% of patients. The second drug increases the activity of the immune response. "This combination represents one of the first experiments with the use of two molecules that allow the use of immune mechanisms in the treatment of oncological diseases. In non–small cell lung cancer, it has demonstrated very impressive clinical activity," says AstraZeneca Executive Director Pascal Soriot. It is important that this combination is also effective for those patients who reluctantly responded to therapy with durvalumab alone. In the portfolio of the AstraZeneca division, Medimmune company, there are a number of other developments, including anti-PD-1 and other drugs that are designed to affect certain receptors, in fact, enhancing or restoring the antitumor immune response. In addition to the fact that research is conducted in the company itself, it enters into partnership agreements with developers implementing interesting projects in this direction.

"In the course of research, we see how we can strengthen the immune response," says William Pao, head of the global oncology department at Roche Pharmaceutical Division. "Now we have several such drugs at the stage of clinical trials. For example, the target for one of them is a macrophage that reduces the activation of a T-lymphocyte. Our goal is to rid the lymphocyte of excessive macrophage care. With certain tumors in the joints, where the number of tumor-associated macrophages is high, the use of our new drug emactuzumab gave a fantastic result: the response rate was 86 percent." Another drug, according to Dr. Pao, acts on the activation of the dendritic cell, so that it, in turn, excites as many T-lymphocytes as possible to fight. Roche has high hopes for the development of so-called bispecific T cells: "These are antibodies that are directed at one of the tumor cell receptors that provides binding to T cells and their activation. After that, the T-cells destroy the tumor cells."

The companies are not only developing innovative drugs for immune therapy, but are also conducting rolling trials of these drugs in combination with already known drugs, for example with traditional chemotherapy or with targeted drugs. A good model for the experiment is non-small cell lung cancer and its subspecies. The fact is that scientists and pharmacists already know many mutations associated with this cancer (up to 70%), targeted drugs have already been created for many of these mutations. "Targeted drugs and new immune drugs are used for patients with specific mutations," says Roy Baines. – And the results are very inspiring. At the company, we are developing more than 30 directions related to drug combinations, 17 of them are at the final stages of research."

Intensifies the attack on cancer and the development of diagnostic tests. At Roche, where two powerful divisions – diagnostic and pharmaceutical - are very closely linked, scientists go hand in hand. They not only develop tests that can give answers to the question with which specific drug or with which combination it is necessary to approach a particular patient, but also at the treatment stage they take samples and examine them in order to control or change treatment regimens. After all, it is known that a tumor is, firstly, heterogeneous, and secondly, extremely changeable: it is important for specialists to know what is happening there, inside, at different stages in order to affect the tumor even more effectively. MSD, in partnership, is also developing tests for immune therapy. According to practical oncologists, they are inspired by new drugs and developments, they have something to encourage their patients.

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29.10.2015