South Korean researchers have identified a new mechanism that reduces the effectiveness of the targeted lymphoma drug rituximab in patients with diffuse large B-cell lymphoma (DLBCL) and proposed a blood-based biomarker capable of predicting treatment response.
Samsung Medical Center announced on July 23 that a research team led by Prof. Kim Seok-jin of the Department of Hematology and Oncology published the findings in the latest issue of Blood Cancer Journal.
Lymphoma is a type of blood cancer that develops when lymphocytes, immune cells responsible for defending the body, become cancerous.
Diffuse large B-cell lymphoma (DLBCL), the most common subtype originating from B lymphocytes, is an aggressive cancer that progresses rapidly but can often be cured with appropriate treatment.
Rituximab is a widely used targeted therapy for DLBCL.
Major rituximab products include Roche Korea’s original drug MabThera and Celltrion’s biosimilar Truxima.
Rituximab works by recognizing and binding to CD20, a marker found on the surface of cancer cells, allowing the body’s immune system to identify and destroy the tumor cells.
However, 40% to 50% of patients develop resistance to the therapy, prompting ongoing research into the underlying causes.
Previous studies have suggested that the loss of the CD20 target is one cause of resistance, but that alone has not fully explained why many patients fail to respond.
The research team identified a previously unknown resistance mechanism in which CD20-positive extracellular vesicles released by tumor cells act as “antigen decoys,” binding to rituximab before the antibody can reach the actual cancer cells.
Instead of binding to its intended target, the antibody is diverted to these decoy vesicles, reducing the amount of rituximab available to attack tumor cells.
Using four-dimensional optical microscopy, the researchers observed rituximab attaching primarily to extracellular vesicles rather than to the surface of lymphoma cells, resulting in reduced antibody binding to the cancer cells themselves.
The team analyzed blood serum from newly diagnosed DLBCL patients and quantified the levels of CD20-positive extracellular vesicles.
In both the training cohort and an independent validation cohort, patients with higher pretreatment levels of these extracellular vesicles had significantly lower disease-specific survival and overall survival.
The biomarker remained an independent predictor of prognosis even after adjusting for the International Prognostic Index (IPI).
Laboratory experiments also showed that tumor-derived CD20-positive extracellular vesicles promoted lymphoma cell growth while reducing rituximab’s anti-cancer activity and immune cell-mediated cytotoxicity.
“This study identifies a new resistance mechanism in which extracellular vesicles in the bloodstream bind to therapeutic antibodies, reducing their anti-tumor effects,” Prof. Kim said. “It also suggests the potential for developing a blood test that can predict rituximab response and patient prognosis before treatment, providing an important foundation for improving antibody therapies and advancing precision medicine.”
