Targeting CD38 with monoclonal antibodies disrupts key survival pathways in paediatric Burkitt's lymphoma malignant B cells.

in Clinical & translational immunology by Kathrin Kläsener, Nadja Herrmann, Liliana Håversen, Timothy Sundell, Martina Sundqvist, Christina Lundqvist, Paul T Manna, Charlotte A Jonsson, Marcella Visentini, Diana Ljung Sass, Sarah McGrath, Kristoffer Grimstad, Alaitz Aranburu, Karin Mellgren, Linda Fogelstrand, Huamei Forsman, Olov Ekwall, Jan Borén, Inger Gjertsson, Michael Reth, Inga-Lill Mårtensson, Alessandro Camponeschi

TLDR

  • This study looked at how two drugs, daratumumab and isatuximab, could help treat a type of cancer called pediatric Burkitt's lymphoma (pBL). These drugs target a protein called CD38, which is highly expressed in pBL cells. The study used patient samples and experiments with a cell line called Ramos to see how these drugs affected cellular proliferation, apoptosis, and the PI3K pathway. Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signaling, reducing cellular proliferation, and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also found a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.

Abstract

Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. analyses of patient samples, combined withexperiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway. Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.

Overview

  • The study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. The study analyzed patient samples and experiments using the Ramos cell line to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis, and the PI3K pathway. Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signaling, reducing cellular proliferation, and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.

Comparative Analysis & Findings

  • Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signaling, reducing cellular proliferation, and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes.

Implications and Future Directions

  • The study emphasizes the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL. Future research should focus on further investigating the efficacy of isatuximab in clinical trials and identifying potential biomarkers for response to CD38-targeting therapies. Additionally, future studies should explore the combination of CD38-targeting mAbs with other therapies to enhance their effectiveness in pBL.
Read Full Article