Release the dogs from the chain
The 2018 Nobel Prize in Medicine was awarded for the discovery of a new principle of cancer treatment
Daria Spasskaya, N+1
After the Nobel Committee awarded prizes in physiology and medicine for purely fundamental developments for two years in a row, this time it finally met the expectations of analysts and awarded the prize for cancer immunotherapy. The prize will be shared by American immunologist James Ellison and his Japanese colleague Tasuku Honjo. The choice of the committee did not surprise anyone – at least, the name of James Ellison has been consistently included in the "shortlist" of nominees for the last few years, according to journalists. In 2016, the Clarivate Analytics agency, which makes a forecast based on the citation of scientists' works, included him in its list of potential laureates. The developments of Ellison and Honjo led to the emergence of a new principle for the treatment of malignant tumors, based on the ability of our own immunity to recognize and destroy cancer cells.
Immunity brakes
The work of immune cells, in this case – T-lymphocytes, balances on the edge between "under-tracking" and "overdoing it". To maintain balance and prevent autoimmune diseases, when lymphocytes begin to attack normal cells of the body by mistake, lymphocytes have a "gas" and a "brake". These are protein receptors on the surface of cells, binding to which certain ligand molecules either activates or suppresses the activity of the immune system to destroy potential "enemies". In general, these regulators are called immunity control points, or "checkpoints". Each group of "checkpoints" (stimulators and inhibitors of immunity) includes more than a dozen molecules, but here we will consider two of them – CTLA-4 and PD-1. Both of these molecules are "brakes" of the immune system.
Cytotoxic T-lymphocytes receive information about what they need to pay attention to from antigen-presenting cells that "show" fragments of foreign proteins to lymphocytes. In order to activate lymphocytes against tumor cells, the antigen-presenting cell must communicate not only with the T-cell receptor, but also with the CD-28 co-stimulatory receptor. CD-28 has an "evil twin brother" CTLA-4, interacting with the same marker as CD-28, but at the same time, on the contrary, suppressing the immune response - namely, the proliferation of T cells and the production of signaling molecules that are responsible for the implementation of the immune response.
If CTLA-4 is "turned off", CD-28 will have no competition and immunity will be activated.
The idea that CTLA-4 acts as a "brake" on immunity belongs, among other things, to Ellison. In 1994, employees of his laboratory at the University of California at Berkeley were working on this receptor in search of a cure for autoimmune diseases. However, Ellison had another idea: instead of strengthening CTLA-4, he suggested blocking it with a specific antibody and thus activating antitumor immunity in mice with carcinoma. The approach worked – the introduction of antibodies slowed down the growth of tumors in mice. In addition, the cured mice developed immunity against this type of cancer – the repeated introduction of malignant cells did not lead to the formation of a tumor. An article with the results of the experiment was published in Science in 1996.
Treatment with an antibody against CTLA-4 slows down tumor growth in mice. The change in tumor size in control animals injected with an antibody unrelated to the receptor is indicated by white circles. The experimental groups were injected with a therapeutic antibody simultaneously with tumor cells (black circles) or on the seventh day after the introduction of tumor cells (white squares). Leach et al / Science 1996.
These and similar experiments on CTLA-4 blockade aroused interest in the industry, and a few years later the approach was tested on humans. In 2011, the American Food and Drug Administration approved the first medical drug aimed at the treatment of malignant melanoma by inhibiting the immune checkpoint – ipilimumab (a monoclonal antibody that binds to the receptor and prevents it from working). So far, this is the only approved drug that works specifically with CTLA-4.
For this work, Ellison was awarded many awards – among them the Lasker Prize, the most prestigious after the Nobel Prize in medicine, and the prize of the National Cancer Research Foundation, and awards from various pharmaceutical companies. We can say that Ellison has received some kind of prize every year since 2011, so this series ended with a Nobel quite naturally.
The second "lever" of immunity – PD-1 – reached the clinic later, although it was opened several years earlier. This merit belongs to Tasuku Honjo, an employee of Kyoto University in Japan. He and his colleagues identified the PD-1 gene, found out that the corresponding protein belongs to the immunoglobulin superfamily, and showed that it is somehow associated with cell death in a tumor cell model. The fact that PD-1 plays the role of a negative regulator of immunity was established only in 2000. In addition, in this work, a partner (ligand) PD-1 was discovered – a protein that was so named, PD-L1 (ligand of PD-1). It was found that cancer cells often produce a lot of PD-L1 protein on their surface. The idea that blocking both PD-1 and PD-L1 can lead to activation of antitumor immunity was confirmed in mice in a 2005 publication.
Already in 2006, the first human clinical trial was launched, but the first anti-PD-1 drug nivolumab was approved for cancer treatment only in 2014. At the same time, a second drug was approved – pembrolizumab from Merck. Among the types of cancer that anti-PD-1 antibodies act against are progressive melanoma, non–small cell lung cancer, renal carcinoma, Hodgkin's lymphoma and others.
Mechanism of action of PD-1 and PD-L1 inhibitors. The T-cell contains on its surface T-cell receptors (TCR) and PD-1 receptors, through which the lymphocyte interacts with both the antigen-presenting cell (APC) and the cancer cell, which has the PD-L1 protein. Antibodies blocking both PD-1 and PD-L1 do not allow the cancer cell to "slow down" the immune response against it. Jun Gong et al / Journal for Immunotherapy of Cancer 2018.
What has changed in cancer treatment
Until recently, cancer therapy was based on three basic principles – surgical intervention, irradiation of the tumor with radiation and antitumor chemotherapy, the purpose of which is relatively non-specific, with rare exceptions, the destruction of rapidly dividing tumor cells with toxic substances. However, already at the beginning of the XX century, scientists realized that tumor cells are the same target of immunity as bacteria and parasites, and made the first attempts to treat tumors by activating immunity. Nevertheless, the idea of anti-cancer immunity was abandoned at some point. The discoveries made in the laboratories of Ellison and Honjo radically changed this idea, and therapy with checkpoint inhibitors, especially antibodies against PD-1 and PD-L1, is now at the forefront of medicine.
"In clinical oncology, this is one of the biggest events in history," says Mikhail Maschan, Deputy Director General of the Dima Rogachev National Research Center for Pediatric Hematology, Oncology and Immunology. "We are just beginning to reap the benefits that the development of this type of therapy has brought. Now five (actually six – approx. N+1) drugs of this group have been registered, and dozens, if not hundreds, of molecules exploiting this principle are in development."
How do these drugs differ from more traditional methods of treatment? As the first results of clinical trials on patients with aggressive melanoma have shown, therapy with the first approved checkpoint inhibitor increased the survival rate of patients by one and a half times compared with standard chemotherapy. In addition, immunotherapy is prescribed to patients in cases when the standard course of chemotherapy did not help or the disease returned. For example, among the types of cancer for which pembrolizumab is approved for treatment are metastatic lung cancer, as well as recurrent head and neck cancer. Chemotherapy does not help many patients with such diagnoses.
"The fact is that in patients with advanced tumors, especially with melanoma, now with the help of a combination of these checkpoint inhibitors, long-term survival, that is, actually recovery, can be achieved in 30-40 percent of cases. With some other tumors, the result is also very much improved," comments Mikhail Maschan. "This is the very beginning of the path, but we already know many types of tumors – lung cancer, melanoma, and a number of others in which therapy has shown effectiveness, but even more – in which it is only being investigated, its combinations with conventional therapies are being investigated. The number of people who have survived thanks to this therapy is measured in the tens of thousands."
Pembrolizumab (Wikimedia Commons).
Not a panacea
Unfortunately, despite promising results, checkpoint inhibitor therapy does not help everyone. For example, the PD-L1 protein is not expressed by cancer cells in all people, therefore, immunotherapy directed against it will not work if there is no protein. There is evidence that this type of therapy helps patients better who, for one reason or another, have an increased likelihood of mutations in DNA, including under the influence of tobacco smoke or radiation. For example, the already mentioned pembrolizumab is recommended as therapy for non-operated or metastatic tumors in patients with DNA repair disorders. This is the first case in cancer therapy when a drug is recommended for the treatment of a tumor only on the basis of the presence of certain mutations, regardless of the type of tumor.
"Cancer is hundreds, if not thousands of different diseases, and each has its own mechanisms and molecular pathways that work at the same time, and no one will come up with one drug that is effective for all types of cancer in all patients. But these drugs help with different types of tumors, because they act not at the level of individual processes in the tumor cell, but at the level of the immune system," comments Maschan.
In addition, the therapy is not without side effects. First of all, these are autoimmune reactions, because the drugs cause the activation of immunity, "let the dogs off the chain," according to Mikhail Maschan. Treatment with checkpoint inhibitors can lead to the development of inflammation of various organs. In addition, the drugs work well on adults, but do not work on children. Finally, treatment is still very, very expensive.
"This revolution mainly affected adult oncology, in pediatric oncology, these studies did not make such a revolution, because children's tumors are biologically arranged differently, the immune system sees them very poorly," explains Maschan. – In Russia, three drugs of this group are officially allowed for use. But, unfortunately, the price of one course of this therapy is quite high, it is measured in tens of thousands of dollars a year. However, Russian biopharmaceutical companies are working on creating domestic versions of these drugs, and it is likely that in the near future they will appear on the market at lower prices. I think that this can be expected in a year or two."
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