Targeting MALT1 for the treatment of diffuse large B-cell lymphoma

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) has an aggressive course and is associated with poor prognosis in the relapsed or refractory setting. ABC-DLBCL is characterized by chronic active signaling of NF-κB, which is dependent on the CARD11-BCL10-MALT1 (CBM) complex. MALT1 is a key effector of the CBM complex and activates canonical NF-κB and AP-1 among other transcription factors via distinct protease and scaffold functions. There is therefore growing interest in therapeutic targeting of MALT1 for B-cell malignancies. Here, we review recent advances in therapeutic targeting of MALT1 for ABC-DLBCL. Covalent and allosteric MALT1 protease inhibitors have been developed which inhibit growth of ABC-DLBCL in preclinical models, and two clinical MALT1 protease inhibitors are being developed in phase I clinical trials. Importantly, these compounds can overcome resistance to BTK inhibitors in preclinical models. Alternative compounds blocking the scaffold effect of MALT1 are also in early preclinical development. Blockade of MALT1 protease activity may have important implications for anti-lymphoma immunity by increasing immunogenicity of ABC-DLBCL cells and also by potentiating anti-lymphoma activity of other immune cells in the lymphoma microenvironment. Together, early data suggest that MALT1 is a promising target for ABC-DLBCL and possibly other B-cell malignancies, and can have lymphoma cell-intrinsic as well as immune-mediated therapeutic effects.