Supplementum 01/2019 Imunoterapie
Martina Spisarová, Bohuslav Melichar
Radek Lakomý, Alexandr Poprach
Alexandr Poprach, Radek Lakomý
Zuzana Střížová, Jiřina Bartůňková
Peter Múdry, Lenka Zdražilová Dubská
MUDr. Martina Spisarová; prof. MUDr. Bohuslav Melichar, Ph.D.
Tumor diseases are one of the most common causes of death worldwide and affect all ages. Current advances in malignant therapy are both in the field of surgical treatment, which remains a key curative method of early stages of the disease, as well as in the field of radiotherapy, chemotherapy and, last but not least, targeted treatments that help us to overcome the limits of standard cancer therapies. Even primarily effective targeted therapy often encounters the development of secondary resistance after a certain period of time. The role of the immune system, or the tumor cells escaping from its surveillance, is unquestionable in the development of cancer. Influencing the individual steps of the immune response seemed to be a very promising method how to influence the course of cancer, and in the last few years, this assumption has been confirmed by an ever-expanding number of diagnoses where modern immunotherapy in patients prolongs survival. The key diagnosis has become a disease that, thanks to its chemoresistance and radioresistance, for decades prompted the discovery of other treatment options.
Prof. RNDr. Václav Hořejší, CSc.
Although the immune system is usually much less efficient in defense against tumors as compared to defense against infections, recent discoveries elucidated the causes of this phenomenon and made it possible to improve the efficiency of anti-tumor immune mechanisms. A number of more or less specific tumor antigens have been identified and several mechanisms involved in resistance of tumors to the immune weapons have been discovered. The formulation of tumor immune editing hypothesis and its validation was essential for current understanding of the complex relationship between the tumor and the immune system. The identification of several levels of immunosuppressive mechanisms has been crucial for understanding of the paradoxical phenomenon of immune protection of tumors. Decades of basic research culminated in development of efficient immunotherapeutic approaches which, after further improvements, have the potential to became major tools of anti-tumor therapies.
Doc. MUDr. Daniel Lysák, Ph.D.
Progress in our understanding of tumor immunology together with advances in cell engineering and cultivation have made possible the production of modified T-lymphocytes expressing the chimeric antigen receptor (CAR). This new technology has emerged as an effective modality in many tumors even for diseases refractory to conventional chemotherapy. The lymphocytes are processed ex vivo and after re-infusion are able to recognize and kill the tumor cells. The most notable success has been achieved with the CAR-T cells specific to CD19 antigen, which possess significant antitumor activity in patients with relapsing and refractory B-lymphoid malignancies (ALL, NHL). CAR-T cell therapy may lead to substantial adverse reactions including the cytokine release syndrome or neurotoxicity effects. The list of targetable antigen and indications is continuously being expanded. The efficacy of treatment is also verified in solid tumors, however the results are less encouraging. The modifications to the CAR structure and the final product are under investigation. The research is also focused on understanding the mechanisms of relapses, reducing toxicities and development of the principles of synthetic biology. CAR therapy is still in an early stage of development and they are many possibilities for improvements in its various aspects for the next years. The article summarizes the current status, challenges and potential future trends of CAR therapy.
MUDr. Radek Lakomý, Ph.D.; MUDr. Alexandr Poprach, Ph.D.
The progress in anticancer immunotherapy has been remarkable in the last decade. The concept of immune checkpoint blocade with monoclonal antibodies (checkpoint inhibitors) has opened a new way in the treatment of cancers. Immune checkpoint inhibitors restore and augment antitumor functions of cytotoxic T cells. Efficacy and acceptable safety of immune checkpoint inhibitors have been demonstrated in many clinical trials. Checkpoint inhibitors are now approved for treatment of variety cancers and intensive research on others is under way. There are still many challenges. More than anything else we urgently need reliable biomarkers of efficacy and toxicity. Then we will be able to better select suitable patients for treatment. Immunotherapy is rightly considered to be the fifth pillar of anticancer treatment, next to surgery, radiotherapy, chemotherapy and targeted therapy.
MUDr. Ondřej Kodet, Ph.D.
Melanoma belongs to significantly immunogenic tumors, allowing for immunological approaches. Melanoma immunotherapy is possibly used in adjuvant administration as well as in metastatic disease. Interferon alpha is used for adjuvant treatment without a significant effect in long-term follow-up. More recently, checkpoint inhibitors (anti-CTLA4, PD1/PD-L1) are used in clinical trials also for adjuvant treatment, which are already standard in metastatic disease. The work discusses the most recent clinical trials and points to the possibilities of combined therapy with targeted therapy. New approaches and future directions for immunotherapy of melanoma are also discussed.
MUDr. Alexandr Poprach, Ph.D.; MUDr. Radek Lakomý, Ph.D.
The checkpoint inhibitors now belong to standard treatment options with metastatic renal cell carcinoma patients and significantly prolong overall survival of these patients. The results of the study phase I with combinations of targeted therapy and immunotherapy are also very promising, high response rates and prolonging of progression-free survivals/overall survivals were reached. But we have to wait for studies phase III results. Immunotherapy is also successful with urothelial cancers patients, especially with responders to this treatment. There is a high need to unify various methods of assessments PD-L1 expression which has both predictive and prognostic value. It was proven that combination of PD-L1 expressions and mutations loads of urothelial tumors improve estimation of response rate to the immunotherapy. The immunotherapy is very expensive, so it is important to have valid and reliable predictive factors. In this review, we summarize the up-to-date results of studies with immunotherapy, with renal cell carcinoma patients and urothelial cancers patients.
Doc. MUDr. Milada Zemanová, Ph.D.
Lung cancer leads to death within 5 years in 85-90% of newly diagnosed cases. Lung carcinomas with high mutation load belong to tumors with a good response to antitumor immunotherapy using checkpoint inhibitors. Monoclonal antibodies against the PD-1 receptor (nivolumab, pembrolizumab) or against the PD-L1 ligand (atezolizumab, durvalumab) have been registered for clinical use in lung tumors. The breakthrough in the second (and the next) line of treatment for advanced non-small cell lung cancer (NSCLC) is previously unattained survival median of over 12 months, benefit is particularly relevant for patients with high PD-L1 expression. A major breakthrough in the treatment of advanced NSCLC in patients with high PD-L1 (TPS > 50%) is the significantly higher potent efficacy of monotherapy with pembrolizumab compared to chemotherapy with median survival over 20 months. In patients with low or totally negative PD-L1 expression, the combination of chemotherapy + immunotherapy is significantly better than chemotherapy alone, with median survival rates in various evaluations of 15.2-23.7 months. A breakthrough in inoperable NSCLC is a significant prolongation of two and three-year survival, a 50% longer survival median, doubling the percentage of potentially cured patients after 20 years of treatment stagnation. Breakthrough in extensive stage small cell carcinoma is a significant prolongation of survival and achievement of significantly more long-term remissions by adding atezolizumab to standard chemotherapy including carboplatin and etoposide.
Doc. MUDr. Martin Doležel, Ph.D.
The recent achievements of both preclinical and clinical immunooncological research have led to an increased interest in the immunomodulatory effect of radiotherapy and the associated necessity of assessing the effect of the combination of immunotherapy and ionizing radiation. An example is the PACIFIC study, which demonstrated that the combination of chemoradiotherapy and the durvalumab inhibitor checkpoint significantly improved the overall survival of non-small cell lung cancer patients at a median of 25.2 months. The enormous amount of ongoing studies is a great promise of new treatment options in the near future.
Prof. MUDr. Vladimír Vonka, DrSc.
Immunological approaches are playing an increasing role in the prophylaxis and therapy of malignant tumors. One of the strategies which are under investigation aims at the development of vaccines directed against tumor-specific antigens or oncogenic viruses. There are two types of anticancer vaccines: prophylactic and therapeutic. Thus far the most significant success has been achieved in the prevention of cancers of viral origin. Several kinds of therapeutic vaccines are presently tested in clinical trials. These include vaccines based on peptides, nucleic acids, dendritic cells, recombinant viruses and killed, genetically modified whole cancer cells. Advantages and disadvantages of each of these different prepartions are briefly discussed. It is the aim of the present research to find out the optimal way of their application.
RNDr. Jan Ženka, CSc.
Intratumoral immunotherapy is based on the use of autologous tumor as a vaccine. Direct injection of small amount of immunostimulators into the tumor creates effective concentrations in situ and decreases their side effects. Our therapeutic approach amplifies the primary effect of innate immunity and creates favourable conditions for involvement of adaptive immunity.
Doc. MUDr. Tomáš Büchler, Ph.D.
The aim of non-specific anti-tumour immunotherapy is to activate innate immunity and enhance adaptive immune responses without targeting specific antigens or a specific receptor. Cytokines were the major class of agents used as non-specific immunotherapy in the treatment of malignancies. Currently, non-specific immunotherapy is used as an adjunct to other types of immune therapies in oncology.
MUDr. Zuzana Střížová, prof. MUDr. Jiřina Bartůňková, DrSc.
The role of the tumor-infiltrating lymphocytes (TIL) and its relationship to prognosis has been extensively studied in multiple cancers. Systematic reviews and meta-analysis have shown a positive correlation between the lymphocyte infiltration and the overall survival (OS) and also have revealed the possibility of predicting therapeutic response to immunotherapy by evaluating the lymphocyte density in the tumor. However, the presence of tumor infiltrating lymphocytes must be described together with the functional features and the phenotypic patterns of the cells. The potential of TIL is evident and therefore, establishing systematic guidelines for evaluation and interpretation of TIL may provide a powerful tool in predicting the survival of the patient and selecting an optimal therapeutic approach.
MUDr. Peter Múdry, Ph.D.; doc. RNDr. Lenka Zdražilová Dubská, Ph.D.
Immunotherapies with dendritic cell vaccines are studied for two decades in children with high risk tumors. Majority of subjects are at late stage of disease and heavily pretreated with immunosupresive therapies. Despite this, laboratory signs of response in humoral and cellular immunity and clinical benefit rate and objective responses are observed. The comparison between studies is limited due to different inclusion criteria, diseases and designs of vaccine manufacturing and route of administration. Further research will be focused on depletion of T regulatory lymphocytes by either metronomic low dose chemotherapy or concomitant treatment with immune check-point inhibitors. High risk subjects early after induction treatment with tumor response to conventional therapies will be included. The first clinical trial experience of treatment with dendritic cell vaccine in children in Czech Republic is discussed.