Searching for therapies increasing the effectiveness of anti-CD20 antibody immunotherapy in in vivo models

In recent years, an inexplicable increase in the incidence of hematopoietic neoplasms has been observed. Currently, the most commonly diagnosed type of leukemia is chronic lymphocytic leukemia (CLL) - neoplastic growth originating from B lymphocytes. The course of chronic lymphocytic leukemia shows significant differences - in some patients the cancer develops slowly and does not require treatment, in others the disease progresses rapidly, drug resistance develops and the disease requires treatment with multi-drug regimens. Due to the advanced age of patients (in Poland, the median age at diagnosis is 72 years), it is extremely important to develop safe therapeutic regimens with the lowest possible side effects. In the haematological community in recent years, the postulate of creating a chemotherapy-free therapy has been repeatedly undertaken. Many physicians are inclined to use targeted therapy in combination with specific inhibitors of signal transduction pathways. The development of such therapies should be preceded by thorough research at the level of cell biology. One example of targeted therapy is the widely used anti-CD20 monoclonal antibody. By binding to the CD20 antigen present on tumor cells, these antibodies activate a number of mechanisms involving the cells of the immune system and leading to tumor elimination. The binding of the antibody to the CD20 molecule causes direct killing of the tumor cell by activating the protein cascade, the so-called complement system and programmed cell death. Therapy with anti-CD20 antibodies also involves the mechanisms of non-specific immune response, such as the cytotoxic effect of NK cells and phagocytosis, i.e. the absorption and digestion of neoplastic cells by macrophages. Anti-CD20 antibodies are well tolerated and have few side effects and are successfully used in multi-drug regimens, but when used alone, they rarely provide a complete cure. Therefore, for years, attempts have been made to increase the effectiveness of anti-CD20 antibodies by combining them with new drugs used in oncology. The results of our experiments published in international scientific journals indicate that the use of certain new compounds used or undergoing clinical trials in hemato-oncology leads to the sensitization of neoplastic cells of established cell lines to the action of anti-CD20 antibodies. Thanks to the cooperation with the Institute of Hematology and Transfusion Medicine in Warsaw, we confirmed our observations in samples obtained from patients with CLL. The next stage of our research should therefore be to verify these observations in an animal model. This is also the purpose of this project. We plan to create mouse models that will allow us to comprehensively assess the therapeutic potential of the combinations we propose. Mouse models, although far from a perfect representation of reality, will allow us to identify favorable and unfavorable interactions between drugs tested by us in the in vitro system. In addition, the project involves the creation of a specialized platform that allows the assessment of parameters important for anti-CD20 antibody therapy. The combination of information obtained from in vitro studies and studies in the mouse model will allow us to obtain a more complete picture of the effectiveness of the combinations we propose. The results obtained may therefore be a premise for undertaking clinical trials of the most promising combinations.