Therapeutic Strategies and Molecular Correlates in Aggressive B-cell Lymphomas

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Diffuse large B cell lymphoma (DLBCL) is comprised of two dominant types- activated B cell-like (ABC) and germinal center B cell-like (GCB). They arise by distinct mechanisms, with ABC selectively acquiring mutations targeting the B cell receptor (BCR) that fosters chronic active BCR signaling. Nuclear factor kappa B (NF-KB) activity sustains viability of ABC but not GCB DLBCL cell lines, and is constitutively activated by signals from the BCR and MYD88 pathways. Activating mutations affecting the BCR subunits CD79a and CD79b molecules, the BCR pathway adapter CARD11, and the toll like receptor (TLR) adaptor protein MYD88 promote NF-KB activity in ABC DLBCL, as does inactivation of tumor necrosis factor, alpha-induced protein 3 (TNFAIP3, also known as A20). Bruton's tyrosine kinase (BTK) links BCR activity to NF-KB and is essential for the survival of ABC lines with chronic active BCR signaling. Ibrutinib is a selective, covalent inhibitor of BTK that kills ABC DLBCL lines by reducing NF-KB. We hypothesized that ibrutinib would be active in ABC but not GCB DLBCL based on genetic and functional evidence that BCR signaling is central to its pathogenesis. The understanding of key survival pathways in B-cell lymphomas have led to the development of strategies that inhibit multiple survival nodes. These include BCL-2, a key inhibitor of apoptosis, B-cell receptor signaling, an important driver of NFKB and inhibitors of downstream activators such as IKB kinase as well as inhibition of the steroidal pathways and CD20. These pathways led to the development of the ViPOR regimen, which has shown high activity in R/R DLBCL as well as follicular lymphoma. Importantly, all agents in this regimen show high levels of synergy based on laboratory investigations. Given it novel mechanisms of action, it has shown a high rate of complete remission in patients who are refractory to standard chemotherapy. We have also focused on other B-cell lymphomas which putatively engage B-cell receptor signaling including mantle cell lymphoma and follicular lymphoma.