Barriers to achieving a cure in lymphoma

Abstract

Lymphoma is a diverse disease with a variety of different subtypes, each characterized by unique pathophysiology, tumor microenvironment, and underlying signaling pathways leading to oncogenesis. With our increasing understanding of the molecular biology of lymphoma, there have been a number of novel targeted therapies and immunotherapy approaches that have been developed for the treatment of this complex disease. Despite rapid progress in the field, however, many patients still relapse largely due to the development of drug resistance to these therapies. A better understanding of the mechanisms underlying resistance is needed to develop more novel treatment strategies that circumvent these mechanisms and design better treatment algorithms that personalize therapies to patients and sequence these therapies in the most optimal manner. This review focuses on the recent advances in therapies in lymphoma, including targeted therapies, monoclonal antibodies, antibody-drug conjugates, cellular therapy, bispecific antibodies, and checkpoint inhibitors. We discuss the genetic and cellular principles of drug resistance that span across all the therapies, as well as some of the unique mechanisms of resistance that are specific to these individual classes of therapies and the strategies that have been developed to address these modes of resistance.

Keywords: Lymphoma; drug resistance; immune therapies; novel therapies; targeted agents.

Figure 1

B cell signaling pathway. The recognition of antigen by the BCR initiates BCR signaling cascade by phosphorylation of CD79, resulting in SRC and non-SRC kinase activation. These kinases in proximal BCR signaling phosphorylate signal molecules such as BTK, PCLγ2, and BLNK, which form signalosome. DAG produced by PCLγ2 activates both Ras-ERK and IKK-NFκB pathways. Another product of PCLγ2, IP₃, activates the calcium-NFAT pathway. Upon the phosphorylation costimulatory molecule, CD19, the activation of the PI3K-AKT pathway is initiated^[1]. The various drugs targeting this pathway are shown, including BTKi, SYKi, SRCi, PI3Ki, mTORi, BTKi, MALT1i, MAPK pathway inhibitors, BH3 mimetics, and exportin inhibitors with the targets for these drugs highlighted in red. BCR: B-cell receptor; CD79: cluster of differentiation 79; SRC: proto-oncogene c-SRC; BTKi: Bruton’s tyrosine kinase inhibitor; PCLγ2: phospholipase C gamma 2; BLNK: B-cell linker; DAG: diacylglycerol; NFAT: nuclear factor of activated T-cells; CD19: cluster of differentiation 19; PI3K-AKT: phosphatidylinositol 3-kinase-protein kinase B; SYKi: spleen tyrosine kinase; SRCi: proto-oncogene c-Src inhibitor; PI3Ki: phosphatidylinositol 3-kinase inhibitor; mTORi: mammalian target of rapamycin inhibitor; MALT1i: mucosa-associated lymphoid tissue lymphoma translocation 1; MAPK: mitogen-activated protein kinase; BH3: B-cell lymphoma-2 homology domain 3.