Targeting MALT1 to Enhance Anti-Lymphoma Immunity and Response to Immunotherapy

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ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell non-Hodgkin lymphoma (B-NHL). The treatment of these diseases remains challenging, with many patients ultimately dying. Despite the clinical success of recent advanced immunotherapies against different tumor types, DLBCLs are largely refractory to these new therapies. The immune resistance mechanisms of these diseases are unclear. The heterogeneity of DLBCLs suggests that their treatment can benefit from precision-medicine approaches. Mutations in the TLR mediator MYD88 and B-cell receptor (BCR) signaling molecules, including CD79B, define the MCD- DLBCL subtype, which displays the greatest aggressiveness and refractoriness to therapies. MYD88 and BCR pro-lymphoma signals are integrated by a downstream molecular complex, whose major functional subunit is MALT1. Targeting MALT1 thus represents an attractive option to specifically interrupt the driver pro-lymphoma signals of these aggressive diseases and block their growth. Our collaborators developed the first selective MALT1 inhibitor (MALT1i) and contributed to the generation of the first MALT1i ever tested in patients (NCT03900598; NCT04876092; NCT04657224). Notably, MALT1 is also active in cells that dampen anti-tumor immunity, specifically immunosuppressive regulatory T cells (Tregs) and exhausted T cells (Tex), which are incapable to react and kill tumor cells. Thanks to our unique access to newly developed MCD- DLBCL mouse models, which harbor an intact immune system, we can now for the first time reliably examine the direct anti-tumor and immune-mediated effects of MALT1is, and their potential for combination with immunotherapy. Our preliminary studies in these models show that MALT1is decrease MCD-DLBCL cells as well as lymphoma-infiltrating Tregs and Tex. Moreover, we find that MALT1is increase MCD-DLBCL antigen presentation and co-stimulatory potential as well as T-cell activation and tumoricidal function, which may overall promote anti-lymphoma T-cell responses. Thus, we hypothesize that pharmacologic MALT1 inhibition in the setting of MCD-DLBCLs will have dual positive anti-tumor effects: (1) limiting tumor proliferation, by interrupting the MYD88 and BCR pro-lymphoma signals and (2) potentiating anti-lymphoma immunity, by counteracting immunosuppressive and dysfunctional T cells and increasing lymphoma cell immunogenicity. Based on this hypothesis, our objective is to establish optimal combinations of MALT1is with immunotherapy able to eradicate otherwise immune evasive aggressive lymphomas. Toward this goal, we will test clinically relevant MALT1is alone and in combination with immunotherapy against MCD-DLBCLs in syngeneic mouse models with normal vs. defective immune system (i.e. lacking specific T-cell subsets/function) to discover the mechanisms by which MALT1 inhibition promotes anti-lymphoma immunity. Moreover, we will perform the first validation that MALT1is can activate T-cell responses in patients enrolled in NCT03900598.