Abstract IA49: MALT1 targeting for B-cell lymphomas
Authors: Lorena Fontan
Journal: Blood Cancer Discovery (2020)

Abstract MALT1 biology and function MALT1 is an oncogene frequently translocated to API2 t(11;18)(q21;q21) or IgH t(14;18)(q32;q21) in MALT lymphomas. MALT1 forms part of the CBM complex along with CARD11 and BCL10. This is a high-order complex where MALT1 acts as a scaffolding protein to recruit TRAF6 and the IKK complex and leads to NF-kappaB activation. MALT1 is also a cysteine protease. We now know 10 substrates of MALT1 (including itself) and 2 neosubstrates for the API2-MALT1 fusion protein. MALT1 substrates include several regulators of NF-kappaB and MAPK activation (A20, CYLD, RELB, and HOIL1), and their cleavage amplifies and/or prolongs activation of these pathways. HOIL1 cleavage by MALT1 might also contribute to negative feedback at late stages of signal transduction. Moreover, MALT1 cleaves at least three RNases that modulate the expression of proinflammatory genes and play an important role in T-cell differentiation. Less is known about their role in B-cell biology. Interestingly, CARD11 and MALT1 have been implicated in glutamine transport and its metabolism and, although their role has not been fully elucidated, they may contribute to the metabolic switch from oxidative phosphorylation to aerobic glycolysis that accompanies T- and B-cell activation. MALT1 knockout mice are immunosuppressed and fail to activate T-cell and B-cell receptors but are generally healthy and fertile. However, older mice tend to develop atopic dermatitis. On the other hand, in MALT1 C472A mice where protease activity is lost while scaffolding activity is intact, T and B cells can activate NF-kappaB signaling downstream of TCR/BCR. However, signaling is reduced, likely due to increased activity of MALT1 targets A20, CYLD, RELB, and HOIL1. These mice develop severe autoimmunity that leads to death and that has been attributed to loss of T-regulatory cells, which are very dependent on MALT1 protease activity for differentiation and maintenance. Loss of T-regulatory cells allows unrestricted T-effector cell function leading to the autoimmune syndrome, which is likely antigen driven because independently generated models showed symptoms in different organ systems. Therapeutic targeting of MALT1 A genome-wide shRNA screen uncovered MALT1 as an essential gene for ABC-DLBCL, and subsequent studies using a substrate mimetic inhibitor of MALT1 determined that ABC-DLBCLs were dependent on its protease activity. These findings arouse great interest in targeting MALT1's protease activity and, in the last 8 years, there have been numerous small molecules developed that target MALT1 through different mechanisms. Active site and allosteric inhibitors have been developed that show activity and efficacy in vivo in ABC-DLBCL xenograft models, serving as proof of concept of the therapeutic value of MALT1 inhibition. The first clinical trial for a MALT1 inhibitor was launched in April 2019 (NCT03900598) and is now open in 32 centers. All efficacy studies published to date are based on xenograft studies in immunodeficient mice. Studies in genetically engineered ABC-DLBCL models will shed light on what will be the effects of MALT1 inhibition in the antitumoral immune response. Recent studies using syngeneic solid tumor models in immunocompetent mice showed decreased engraftment of tumors in mice lacking MALT1 protease activity. Moreover, use of a MALT1 inhibitor in combination with PD1 blockage greatly enhanced each other's activity, particularly in highly immunogenic tumors. This effect was attributed to the effects of MALT1 on T-regulatory cells, but deeper mechanistic studies are needed to fully understand the mechanisms at play. Nonetheless, these results suggest that MALT1 inhibition could have both tumor-intrinsic and -extrinsic effects that could cooperate to kill ABC-DLBCL. If general effects over the antitumoral immune response are confirmed, MALT1 inhibition could have a broader application as adjuvant for other immune-oncology approaches in cancer. Little is known to date on what mechanisms of resistance could be deployed by tumor cells to escape MALT1 inhibition. However, based on what is known for BTK and other signaling mediators, resistance will likely arise and combinatorial regimens will be needed to attain durable responses and maximal effectiveness. Our recent work on combinations anchored in MALT1 inhibition showed that BCR, PI3K, and TLR directed inhibitors were either additive or synergistic with MALT1 inhibition. MALT1/PI3Kdelta-i combinations showed enhanced but not durable responses in vivo. Tumors in mice treated with this combinatorial regime resumed growth while in treatment and displayed active NF-kappaB and MTORC1 signaling. This study revealed that MTORC1 activation could constitute a critical feedback mechanism limiting the effect of MALT1 inhibitors. In concordance, a MALT1/MTORC1 combinatorial regime suppressed MTORC1 activation and was highly effective in vivo, leading to tumor regression and significant enhanced survival after only one cycle of treatment. Future studies using clinical candidates and patient samples will further our understanding of this mechanism and elucidate other mechanisms that can be deployed by cells to overcome MALT1 inhibition and will help shape the future of MALT1 inhibition-centered oncologic regimens. Citation Format: Lorena Fontan. MALT1 targeting for B-cell lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA49.