Increasing membrane target expression to improve immunotherapy response in B-cell non-Hodgkin lymphoma (B-NHL)
B-cell non-Hodgkin lymphoma (B-NHL) is the most common hematological
malignancy worldwide, responsible for 250,000 deaths annually. Immunotherapy with anti-CD20 antibody rituximab, is a cornerstone drug in the treatment of many B-NHL patients, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). However, rituximab-based therapy (R-CHOP) is linked to ~40% refractory/relapse (R/R) disease with poor prognosis. This is partly due to a downregulation in the surface expression of CD20. CD22 and CD37 represent other promising B-cell membrane proteins that are currently investigated as novel therapeutic targets for B-NHL. This project is aimed at uncovering key genetic elements that control the surface expression of CD20, CD22 and CD37. Identifying druggable targets and compounds that can upregulate the surface expression of these targets, may sensitize (R/R) B-NHL tumors and improve immunotherapy efficacy in patients with B-NHL.
We performed a high-throughput compound screen to identify drugs that can increase the surface expression of therapeutic targets in DLBCL and CLL cell lines.
Identification of critical regulators of CD20, CD22 and CD37 expression using unbiased candidate-based approaches will 1) increase our understanding into molecular pathways underlying the expression of these immunotherapeutic targets and 2) define novel combination therapies which will allow us to increase surface expression of targets and improve the efficacy of treatment for B-NHL patients.
The compounds identified through the high-throughput screen increase the expression of CD20 and leads to improved antibody mediated tumor cell death.