Share
27. July 2021
New findings might help reduce the toxicity of the treatment and also its cost
Press release;
A team of scientists led by Assoc. Prof. Marek Mraz from CEITEC Masaryk University and the University Hospital Brno, recently published a scientific study in which they challenged the existing knowledge about the two drugs commonly combined (idelalisib and rituximab) in the treatment of patients with chronic lymphocytic leukaemia. The scientists explain that after the administration of idelalisib, cell surface levels of CD20 are significantly reduced. CD20 is a molecule that is targeted by the rituximab antibody in therapeutic use. Czech scientists show that this clinically approved therapeutic combination of idelalisib and rituximab is unlikely to bring the desired clinical benefit, in comparison with the application of idelalisib alone. This study, published in the prestigious scientific journal Haematologica, is likely to have a major impact on future clinical trials with idelalisib and its combination with anti-CD20 antibodies and possibly also on other therapeutic combinations.
The first author of the study, Veronika Sandova, described a completely new mechanism for regulating CD20 gene expression, which has important implications for the treatment of patients with chronic lymphocytic leukaemia (CLL), which is the most common leukaemia in adults. In this and other related diseases, the drug rituximab is used in order to target a cell surface molecule called CD20. Sufficient CD20 protein on the cell surface is required for the positive therapeutic effect of rituximab, but for the last two decades, it remains unclear how CD20 levels on tumour cells are regulated. At the same time, other drugs may theoretically decrease (or possibly increase) CD20 levels, thereby adversely affecting the function of the rituximab in cases where the level of the CD20 molecule is lower on tumour cells.
"For the first time, we have shown that when tumour B cells interact with T cells, a specific cytokine signalling pathway is activated in tumour B cells, which activates the CD20 gene, which then reaches the cell surface as a protein where it can serve as a target for therapeutic antibodies such as rituximab. The research team described that interleukin 4 produced by T lymphocytes is captured by receptors on the surface of malignant B lymphocytes, where it triggers intracellular signalling mainly through the STAT6 protein, which activates the CD20 transcription in the cell nucleus. Idelalisib is an inhibitor of the B cell receptor signalling, namely PI3K protein. PI3K serves as an important member of the signalling cascade leading to the regulation of cell division and tumour B cell survival. In the treatment of chronic lymphocytic leukaemia, the combination of idelalisib together with rituximab has been used in the Czech Republic and worldwide since 2014,” explains Veronika Sandova, the first author of the study.
"For the first time, we have demonstrated that idelalisib disrupts interleukin 4-STAT6 signalling, and reduces the amount of CD20 protein on the cell surface. The results of our study therefore suggest that the currently used therapeutic combination of rituximab with idelalisib may not have the expected therapeutic benefits, thus opening up space for new clinical studies on the suitability of the combination of anti-CD20 antibodies with PI3K inhibitors such as idelalisib,” adds the leading researcher of this study Marek Mraz. Some studies, including those of the Marek Mraz Research Group, previously showed that the combination of rituximab with other BCR inhibitors might not be completely effective. Marek Mraz and his team also showed that the BCR inhibitor ibrutinib reduces CD20 levels by affecting interactions in the tumour microenvironment. This suggested that there is a possibility of a similar effect of idelalisib. In the case of idelalisib, the research team used patients’ samples with chronic lymphocytic leukaemia who were treated only with idelalisib, and not with the usual combination of rituximab and idelalisib. Scientists compared CD20 levels in those samples before and after idelalisib treatment in vivo. At the same time, patient samples were exposed to in vitro (in laboratory settings) signalling studies, thus revealing a new mechanism of CD20 regulation by interleukin 4 itself, and also showed how idelalisib alters CD20 levels on the cell surface.
"Our study confirms that in order to apply an effective treatment of chronic lymphocytic leukaemia, it is necessary to understand the molecular processes that take place at the level of the malignant B lymphocyte and their function within the tumour microenvironment. It is the tumour microenvironment that is absolutely essential for the survival and proliferation of tumour cells. At the same time, it is necessary to understand in detail how each treatment works in combination with other used drugs to achieve the greatest possible therapeutic benefit for patients. Our data suggest the possibility that it is not effective and necessary to combine idelalisib with rituximab for a clinical effect in CLL, and use of single-agent idelalisib could potentially reduce the toxicity as well as the cost of the treatment. Further clinical trials in this area will be needed,” concludes Marek Mraz.