Assoc. Dr. Zhelyazko Arabadzhiev is the chairman of the Bulgarian Scientific Society of Immuno-Oncology. He is the head of the Medical Oncology Clinic of Acibadem City Clinic UMBAL Tokuda. He defended his doctoral dissertation and is the author of two monographs devoted to the immunotherapy of oncological diseases. He is a member of the Cancer Mission to the European Commission. – Associate Professor Dr. Arabadjiev, what is immuno-oncology as a field of medical science? The immune system is the body’s natural defense system that helps protect it from infections, cancer and other diseases. When a different (foreign) organism, such as a bacterium, enters the body, the immune system recognizes it and attacks it to prevent it from causing harm. This process is called an immune response. Because cancer cells are very different from normal cells in the body, the immune system attacks them when it is able to recognize them. However, cancer cells often find ways to disguise themselves as normal cells, so the immune system does not always recognize them as dangerous. Also, like viruses, they can change (mutate) over time and thus evade the immune response. Moreover, the body’s natural immune response to cancer cells is not always strong enough to destroy them. Immuno-oncology therapies aim to activate our immune system, enabling it to recognize cancer cells and destroy them by providing a long-term memory for the immune system itself so that it can continuously adapt to the cancer over time and thus provide sustained, long-term response. So, broadly speaking, immuno-oncology is a field of medical science focused on therapeutic approaches that use the activation of our own immune system to fight cancer. Data from clinical trials show that the effects of immuno-oncology therapies can last a long time, “training” our immune system to fight cancer cells, even after the remission phase. This characteristic of immuno-oncology therapies has made them a new hope for cancer patients, offering them long-term and quality survival, even in cases of unfavorable prognosis. In general, immuno-oncology and immunotherapies are entering increasingly successfully in the treatment of malignant diseases of the blood, so-called hematological malignancies, as well as in the therapy of solid malignant tumors. This share of medicine is particularly relevant today and its role is expected to grow extremely rapidly in the coming decades. This is also the main reason for founding the Bulgarian Scientific Society of Immuno-oncology, which I have the honor to chair. Its main goal is to increase our knowledge in the fight against cancer and to build the connections between the individual directions in the field of immuno-oncology. – What is the mechanism of action of immunotherapies,which are used to treat cancer? Immunotherapy for solid tumors has entered the treatment of cancer patients extensively in the past 5 years and, in addition to changing the prognosis and prolonging the lives of these patients, in some cases even led to their cure. Modern drugs, which oncologists call immunotherapy, actually change (modulate) the body’s immune response by targeting it specifically to tumor cells, so that control processes suppressing the activity of T cells against tumor cells are blocked. T-cells are those cells in the human body that have the ability to eliminate cancer cells naturally, ie. have a strong cytotoxic effect. On the other hand, tumor cells themselves possess the ability to evade recognition by the body’s T cells. And this is precisely the place of therapeutic approaches in immuno-oncology, which enable T-cells to identify cancer cells, classify them as dangerous for the body and fight them. Antitumor immunotherapy is represented by products that suppress certain receptors on tumor and immune cells (eg PD-1, PD-L1, CTLA-4), thereby achieving a more powerful antitumor immune response against cancer cells. These medicinal products are called checkpoint inhibitors or the so-called immune checkpoint inhibitors. Of course, immunotherapy today is represented by five different pharmacological and biological classes of medicinal products. In addition to the inhibitors of immune checkpoints, which have already been discussed, monoclonal antibodies, adoptive cell technologies, oncolytic viruses and anti-tumor vaccines are also used in practice. Monoclonal antibodies are artificial antibodies designed to be directed against a single, specific known antigen, often a protein on the surface of cancer cells. Adoptive cell technologies are related to cell therapies consisting of adoptive tumor infiltrating lymphocytes (TIL), which are made individually for each patient, and have shown very good results in the treatment of blood cancer and skin cancer. Oncolytic viruses are the most commonly known viruses, such as human herpes simplex virus 1, which, through genetic modification, is modified to infect only tumor cells without affecting the rest of the healthy cells in the patient’s body, which in turn leads to the death of tumor cells, and the released viruses enter the body’s bloodstream again and thus infect other tumor cells. Antitumor vaccines are also a new and cutting-edge field in immuno-oncology. These are vaccine products based on tumor cell-derived genetic information (DNA and RNA) or proteins produced by tumors. Vaccination with these products leads to specific immunity against the tumor cells from which they are produced, and this specificity ensures complete and long-lasting destruction of cancer cells. Of course,currently the most widely used in oncology practice are immune checkpoint inhibitors. The mechanism of action of these drugs is based on the discovery of scientists James P. Allison and Tasuku Honjo, who received the 2018 Nobel Prize in Medicine. As I have already explained, the principle of the therapy is that the tumor cell blocks a specific protein on the surface of the T-cell / the so-called checkpoints/ which otherwise binds to tumor cells and does not recognize them as dangerous for the body. Unfortunately, after blocking the checkpoints, the immune system may start to misrecognize some of the healthy cells in the body and begin to eliminate them as well, which can lead to some unwanted autoimmune side effects for the patient. – In which oncological diseases are immunotherapies already applied? Not all solid tumors are immunogenic and are affected by the immune system. Therefore, immunotherapy is not applied to all types of cancer, but among those in which we have good results are skin cancer (malignant melanoma), solid malignant tumors of the lungs, bladder, breast, liver, colon, tumors on the head and neck. Immunotherapy is also an effective treatment in the field of malignant blood diseases (hematological diseases) – in lymphomas and leukemia. Fortunately, there is growing evidence from clinical trials suggesting the effectiveness of immunotherapies in pancreatic, prostate, ovarian and endometrial carcinomas as well. Of course, the efficacy of immunotherapy is directly dependent on the type of tumor cells and the different locations. – What are the advantages of immunotherapy over classical chemotherapy? The advantages of immunotherapy are closely related to its specific mechanism of action. If in chemotherapy tumor cells are destroyed during their division cycle, but at the same time healthy cells of the patient’s body are also damaged, then in immunotherapy the antitumor effect is directed only at cancer cells. This is where the various side effects of chemotherapy and immunotherapy come from. Hair loss, nausea and vomiting, fatigue and lower extremity pain accompanying chemotherapy are not at all characteristic of immunotherapy. On the other hand, immunotherapy comes with other side effects. As I mentioned, it is associated with some unwanted autoimmune side effects and can lead to hypo- or hyperthyroidism, pneumonia, colitis, hepatitis, etc. According to a mechanism that is still not fully specified, immunotherapy also targets healthy cells, especially of the thyroid gland, lungs, colon or liver. The treatment of these adverse, immune-related effects is with corticosteroids and other immunosuppressants, and often these secondary autoimmune processes that occur are completely reversible. In this sense, it is important to knowthat patients with chronic autoimmune diseases such as Crohn’s disease, idiopathic pulmonary fibrosis or rheumatoid diseases are not suitable for antitumor immunotherapy. Among the advantages of immunotherapy, which at this stage is administered only as intravenous infusions, is that it is easily tolerated by patients and, because it does not produce the usual side effects, as with chemotherapy, it does not worsen, but rather improves, the quality of life of patients. – What specialized research should be done to apply immunotherapy in the treatment of a specific patient? In personalized oncology, it is extremely important to find a reliable indicator (biomarker) that predicts whether a drug will be effective in the corresponding patient and the corresponding tumor. In immunotherapy at this stage, such a biomarker is the expression of the so-called PDL1 ligand tested from the material taken from the biopsy or from the surgically removed tumor. It is believed that the higher the percentage of PDL1 on the tumor cells, the more successful the treatment with the checkpoint inhibitors would be. We should also mention that there are malignant tumors in which immunotherapy treatment is not determined by PDL1 testing – for example, in melanoma of the skin, as well as in head and neck tumors, bladder, etc. In the case of the latter, a more complex indicator is examined. According to recent data from clinical trials with new immunotherapies, it became clear that in the near future, new possibilities for impacting tumor cells will also be investigated, which will subsequently also be used as a kind of biomarkers for the efficacy of such therapies in the particular patient. – Is immunotherapy available for Bulgarian oncology patients? With reassurance, we can say that in Bulgaria at the moment the checkpoint inhibitors approved in Europe are available for most tumor localizations. However, the analysis of the approval rates of new antitumor medicinal products shows a significantly longer approval time and availability of these drugs to the Bulgarian patient, and this applies not only to new immunotherapies, but also to new indications for the treatment of already approved ones. The registration of new oncotherapies in the last 5 years has been very dynamic. Therefore, there must be a clear vision on the part of the regulator and the state to provide adequate regulatory framework so that the process happens quickly enough. It is also necessary to have sufficient financial security in the budget of the NHIF to guarantee 100% reimbursement of all new therapies for cancer patients in Bulgaria.to implement immunotherapy in the treatment of a particular patient? In personalized oncology, it is extremely important to find a reliable indicator (biomarker) that predicts whether a given drug will be effective in the corresponding patient and the corresponding tumor. In immunotherapy at this stage, such a biomarker is the expression of the so-called PDL1 ligand tested from the material taken from the biopsy or from the surgically removed tumor. It is believed that the higher the percentage of PDL1 on the tumor cells, the more successful the treatment with the checkpoint inhibitors would be. We should also mention that there are malignant tumors in which immunotherapy treatment is not determined by PDL1 testing – for example, in melanoma of the skin, as well as in head and neck tumors, bladder, etc. In the case of the latter, a more complex indicator is examined. According to recent data from clinical trials with new immunotherapies, it became clear that in the near future, new possibilities for impacting tumor cells will also be investigated, which will subsequently also be used as a kind of biomarkers for the efficacy of such therapies in the specific patient. – Is immunotherapy available for Bulgarian oncology patients? With reassurance, we can say that in Bulgaria at the moment the checkpoint inhibitors approved in Europe are available for most tumor localizations. However, the analysis of the approval rates of new antitumor medicinal products shows a significantly longer approval time and availability of these drugs to the Bulgarian patient, and this applies not only to new immunotherapies, but also to new indications for the treatment of already approved ones. The registration of new oncotherapies in the last 5 years has been very dynamic. Therefore, there must be a clear vision on the part of the regulator and the state to provide adequate regulatory framework so that the process happens quickly enough. It is also necessary to have sufficient financial security in the budget of the NHIF to guarantee 100% reimbursement of all new therapies for cancer patients in Bulgaria.to implement immunotherapy in the treatment of a particular patient? In personalized oncology, it is extremely important to find a reliable indicator (biomarker) that predicts whether a drug will be effective in the corresponding patient and the corresponding tumor. In immunotherapy at this stage, such a biomarker is the expression of the so-called PDL1 ligand tested from the material taken from the biopsy or from the surgically removed tumor. It is believed that the higher the percentage of PDL1 on the tumor cells, the more successful the treatment with the checkpoint inhibitors would be. We should also mention that there are malignant tumors in which immunotherapy treatment is not determined by PDL1 testing – for example, in melanoma of the skin, as well as in head and neck tumors, bladder, etc. In the case of the latter, a more complex indicator is examined. According to the latest data from clinical trials with new immunotherapies, it became clear that in the near future, new possibilities for impacting tumor cells will also be investigated, which will subsequently also be used as a kind of biomarkers for the efficacy of such therapies in the particular patient. – Is immunotherapy available for Bulgarian oncology patients? With reassurance, we can say that in Bulgaria at the moment the checkpoint inhibitors approved in Europe are available for most tumor localizations. However, the analysis of the approval rates of new antitumor medicinal products shows a significantly longer approval time and availability of these drugs to the Bulgarian patient, and this applies not only to new immunotherapies, but also to new indications for the treatment of already approved ones. The registration of new oncotherapies in the last 5 years has been very dynamic. Therefore, there must be a clear vision on the part of the regulator and the state to provide adequate regulatory framework so that the process happens quickly enough. It is also necessary to have sufficient financial security in the budget of the NHIF to guarantee 100% reimbursement of all new therapies for cancer patients in Bulgaria.that in the near future, new possibilities for influencing tumor cells will also be investigated, which will subsequently also be used as a kind of biomarkers for the efficacy of such therapies in the specific patient. – Is immunotherapy available for Bulgarian oncology patients? With reassurance, we can say that in Bulgaria at the moment the checkpoint inhibitors approved in Europe are available for most tumor localizations. However, the analysis of the approval rates of new antitumor medicinal products shows a significantly longer approval time and availability of these drugs to the Bulgarian patient, and this applies not only to new immunotherapies, but also to new indications for the treatment of already approved ones. The registration of new oncotherapies in the last 5 years has been very dynamic. Therefore, there must be a clear vision on the part of the regulator and the state to provide adequate regulatory framework so that the process happens quickly enough. It is also necessary to have sufficient financial security in the budget of the NHIF to guarantee 100% reimbursement of all new therapies for cancer patients in Bulgaria.that in the near future, new possibilities for influencing tumor cells will also be investigated, which will subsequently also be used as a kind of biomarkers for the efficacy of such therapies in the specific patient. – Is immunotherapy available for Bulgarian oncology patients? With reassurance, we can say that in Bulgaria at the moment the checkpoint inhibitors approved in Europe are available for most tumor localizations. However, the analysis of the approval rates of new antitumor medicinal products shows a significantly longer approval time and availability of these drugs to the Bulgarian patient, and this applies not only to new immunotherapies, but also to new indications for the treatment of already approved ones. The registration of new oncotherapies in the last 5 years has been very dynamic. Therefore, there must be a clear vision on the part of the regulator and the state to provide adequate regulatory framework so that the process happens quickly enough. It is also necessary to have sufficient financial security in the budget of the NHIF to guarantee 100% reimbursement of all new therapies for cancer patients in Bulgaria.