Targeting the tumor microenvironment in chronic lymphocytic leukemia

The tumor microenvironment (TME) plays an essential role in the development, growth, and survival of the malignant B-cell clone in chronic lymphocytic leukemia (CLL). Within the proliferation niches of lymph nodes, bone marrow, and secondary lymphoid organs, a variety of phenotypically and functionally altered cell types, including T cells, natural killer cells, monocytes/macrophages, endothelial and mesenchymal stroma cells, provide crucial survival signals, along with CLL-cellinduced suppression of antitumor immune responses. The B-cell receptor pathway plays a pivotal role in mediating the interaction between CLL cells and the TME. However, an increasing number of additional components of the multifactorial TME are being discovered. Although the majority of therapeutic strategies employed in CLL hitherto have focused on targeting the leukemic cells, emerging evidence implies that modulation of microenvironmental cells and CLL-TME interactions by novel therapeutic agents significantly affect their clinical efficacy. Thus, improving our understanding of CLL-TME interactions and how they are affected by current therapeutic agents may improve and guide treatment strategies. Identification of novel TME interactions may also pave the road for the development of novel therapeutic strategies targeting the TME. In this review, we summarize current evidence on the effects of therapeutic agents on cells and interactions within the TME. With a growing demand for improved and personalized treatment options in CLL, this review aims at inspiring future exploration of smart drug combination strategies, translational studies, and novel therapeutic targets in clinical trials

Non-coding RNAs as therapeutic agents : The future of therapy

Non-coding RNA (ncRNA) therapeutics are based on short oligonucleotides, both naturally occurring and artificial, which target RNA in a site-specific way to modulate gene expression. As of today, 12 synthetically produced ncRNA-based drugs are available on the market in the US and Europe, and there is a possibility of more to be approved in the near future. This project is ordered by Cytiva, a global life science company, with the aim to present an overview of the current ncRNA therapeutics field. The aim is to give Cytiva a clear indication of what type of products for oligonucleotide synthesis are requested by their clients in the pharmaceutical industry. ncRNAs were examined extensively for their potential as therapeutic agents during our literature study. Based on the number of approved drugs, clinical trials, and our overall impression of future potential, we selected the following four ncRNAs; Antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNA (miRNA), and small nuclear RNA (snRNA). Among these, the most promising ncRNAs for therapeutic use are siRNA and ASO which usually are 20-30 nucleotides long. The most common modifications to improve drug-like properties are modifications to the backbone, sugar modifications at position 2, and methylation of nucleobases at position 5 of the oligonucleotide. In addition, ncRNA-based drugs on the market today are delivered either through non-viral mechanisms or without a delivery system. The conclusion that can be drawn from our report is the importance of being able to synthesize chemically modified ASOs and siRNA on a large scale to meet the future demand of the pharmaceutical industry

Non-coding RNAs as therapeutic agents : The future of therapy

Non-coding RNA (ncRNA) therapeutics are based on short oligonucleotides, both naturally occurring and artificial, which target RNA in a site-specific way to modulate gene expression. As of today, 12 synthetically produced ncRNA-based drugs are available on the market in the US and Europe, and there is a possibility of more to be approved in the near future. This project is ordered by Cytiva, a global life science company, with the aim to present an overview of the current ncRNA therapeutics field. The aim is to give Cytiva a clear indication of what type of products for oligonucleotide synthesis are requested by their clients in the pharmaceutical industry. ncRNAs were examined extensively for their potential as therapeutic agents during our literature study. Based on the number of approved drugs, clinical trials, and our overall impression of future potential, we selected the following four ncRNAs; Antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNA (miRNA), and small nuclear RNA (snRNA). Among these, the most promising ncRNAs for therapeutic use are siRNA and ASO which usually are 20-30 nucleotides long. The most common modifications to improve drug-like properties are modifications to the backbone, sugar modifications at position 2, and methylation of nucleobases at position 5 of the oligonucleotide. In addition, ncRNA-based drugs on the market today are delivered either through non-viral mechanisms or without a delivery system. The conclusion that can be drawn from our report is the importance of being able to synthesize chemically modified ASOs and siRNA on a large scale to meet the future demand of the pharmaceutical industry

Changes in primary and secondary hemostasis in patients with CLL treated with venetoclax and ibrutinib

Bleeding is a common adverse event following ibrutinib monotherapy. However, it remains unclear how hemostasis is affected by venetoclax in combination with ibrutinib. Here we investigated hemostasis in patients with chronic lymphocytic leukemia (CLL) at baseline, during ibrutinib monotherapy, and during venetoclax and ibrutinib combination therapy or venetoclax monotherapy. Primary hemostasis, assessed by Multiplate using adenosine diphosphate (ADP), arachidonic acid (AA), and thrombin receptor agonist peptide (TRAP-6), was impaired in all CLL patients at baseline, remained unchanged upon ibrutinib monotherapy, and improved significantly following venetoclax added to ibrutinib or as monotherapy. Secondary hemostasis assessed by thromboelastography (TEG) was normal and unchanged throughout treatment. The frequency of clinical bleeding events was the highest during ibrutinib monotherapy, in line with the demonstrated improved primary hemostasis upon addition of venetoclax, thus pointing toward a treatment option for CLL patients with increased bleeding risk