Targeted Therapies in Adult B-Cell Malignancies

Abstract

B-lymphocytes are programmed for the production of immunoglobulin (Ig) after antigen presentation, in the context of T-lymphocyte control within lymphoid organs. During this differentiation/activation process, B-lymphocytes exhibit different restricted or common surface markers, activation of cellular pathways that regulate cell cycle, metabolism, proteasome activity, and protein synthesis. All molecules involved in these different cellular mechanisms are potent therapeutic targets. Nowadays, due to the progress of the biology, more and more targeted drugs are identified, a situation that is correlated with an extended field of the targeted therapy. The full knowledge of the cellular machinery and cell-cell communication allows making the best choice to treat patients, in the context of personalized medicine. Also, focus should not be restricted to the immediate effects observed as clinical endpoints, that is, response rate, survival markers with conventional statistical methods, but it should consider the prediction of different clinical consequences due to other collateral drug targets, based on new methodologies. This means that new reflection and new bioclinical follow-up have to be monitored, particularly with the new drugs used with success in B-cell malignancies. This review discussed the principal aspects of such evident bioclinical progress.

Heterogeneity of Toll-like receptor 9 signaling in B cell malignancies and its potential therapeutic application

“…B-cell malignancies are clinically and biologically heterogeneous, and they comprise a diverse spectrum of acute or chronic leukemia and lymphoma subtypes. Over the last few decades, advances in chemotherapy regimens, monoclonal antibodies, and targeted therapies have led to a dramatic improvement in the treatment of these disorders [ 1 , 2 ]. The availability of specific antigens and the easy accessibility of the immune system to these diseases may make the immunotherapy of B-cell malignancies possible.…”

Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets

“…It could be said that most of the LSAs are clinically validated targets in antibody-based therapy. CD20 is a LSA exclusively expressed on B-cells membrane and on the majority of malignant B-cells ( 6 , 9 ). The “blockbuster” antibody rituximab is the first-in-class anti-CD20 mAb approved for the treatment of B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL); it is by far the most important mAb used in hematological malignancies ( 10 – 12 ).…”

“…The success of anti-CD20 mAbs has encouraged drug developers to propose novel LSAs, such as CD19, CD22, or CD79b (Table 2 ) ( 24 – 26 ). Despite these LSAs representing potential candidates for the treatment of B-cell cancers, antibodies directed to CD19 (MOR00208, inebilizumab, or MDX-1342) or CD22 (epratuzumab) have yielded only modest responses in clinical studies ( 9 ). This low efficacy has been attributed to high Ag internalization rates on mAb ligation ( 3 ).…”

“…Limited clinical efficacy of some mAbs targeting LSAs and the advent of patients with refractory diseases to therapies directed to LSAs boosted the research on many NLSAs with a relevant role in the pathogenesis of cancer, especially in B-cell malignancies ( 9 , 34 ). Moreover, in some disorders the lack or loss of LSA expression in cell membrane may preclude the use of antibodies, thus prompting research of other potential therapeutic targets.…”

CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents

“…In the peripheral blood, B cell subsets can be distinguished corresponding to different stages of differentiation, maturation and activation, which are characterized by the expression of different surface markers, such as CD19, CD20, and CD27 ( Maecker et al, 2012 ; Leandro, 2013 ). CD19 is a special surface marker for B cells ( Rossi, 2015 ). CD20 is expressed during B cell differentiation and lost during terminal differentiation to plasma cells.…”