Abstract Constitutive activation of the B-cell receptor (BCR) pathway drives non-Hodgkin lymphomas. MALT1 is a key mediator of NF-κB signaling downstream of B- and T-cell receptors. Herein, we report development of safimaltib (JNJ-67856633), a selective, allosteric inhibitor of MALT1 protease. The crystal structure of safimaltib bound to MALT1 was determined, and enzyme kinetic studies were performed to characterize its inhibitory mechanism. Sub-micromolar doses of safimaltib inhibited growth of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines with activation of NF-κB signaling and models mimicking BTK inhibition resistance. Notably, activating mutations in BCR-pathway components were strongly associated with safimaltib response in vitro. Safimaltib demonstrated efficacy in DLBCL and MCL mouse models and synergy with a BTK inhibitor. Safimaltib was well tolerated in preclinical immunocompetent animal models with a safety profile supporting MALT1 targeting in humans. Overall, these results provide rationale for the first-in-human MALT1 inhibitor clinical trial.
Summary: Safimaltib, a selective allosteric MALT1 protease inhibitor, shows potent antitumor activity in preclinical and clinical studies of B-cell non-Hodgkin lymphomas. See related article by Philippar et al., p. XX See related article by Hertzberg et al., p. XX
Summary: Cell and immune therapies have transformed the outcomes of patients with lymphoma, but the majority of patients do not have durable benefit. Here, we provide our perspective on key challenges in personalizing cell and immune therapy approaches for lymphoma through discovery, validation, and clinical deployment of microenvironment classification.
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) affect most patients receiving axicabtagene ciloleucel (axi-cel) for relapsed or refractory large B-cell lymphoma (LBCL). Based on pre-clinical data, we hypothesized that prophylactic IFN-γ blockade could prevent toxicity without impairing efficacy. We initiated an open-label phase 2 trial (NCT06550141) evaluating single-dose emapalumab one day before axi-cel. Here, we report the first two patients to caution against the pre-emptive emapalumab use prior axi-cel: Both developed treatment-refractory toxicities including high-grade ICANS and overlapping CRS-IEC-HS requiring multiple immunomodulatory agents. CAR T-cell expansion exceeded levels reported in ZUMA-1 and a standard-of-care axi-cel cohort at our institution. Despite therapeutic emapalumab and suppressed free IFN-γ, IL-2 and sIL-2R were markedly elevated, suggesting CRS was driven independent of IFN-γ. Both patients achieved complete responses, suggesting preserved efficacy. Given the unanticipated severity and refractoriness of toxicities, recruitment with this design was discontinued and the protocol was amended.
Summary: In this issue of Blood Cancer Discovery, Corona, Gillmor, and colleagues show that quantitative CD19 density measured before chimeric antigen receptor (CAR) T-cell infusion stratifies progression-free survival in large B-cell lymphoma, yet low antigen density rarely reflects a genetic lesion at the CD19 locus itself, suggesting that other mechanisms of CD19 downregulation may promote CAR T-cell escape. Moreover, Newsam and colleagues offer one explanation—recurrent del(3p21.31)/RHOA loss that results in decreased CD19 in trans and impairs CAR T-cell efficacy. See related article by Corona, Gillmor, and colleagues, p. XX . See related article by Newsam and colleagues, p. XX .
