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

摘要 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的B细胞非霍奇金淋巴瘤（B-NHL）。的 这些疾病的治疗仍然具有挑战性，许多患者最终死亡。尽管临床 最近针对不同肿瘤类型的先进免疫疗法的成功，DLBCL在很大程度上是难治的。 这些新疗法。这些疾病的免疫抵抗机制尚不清楚。异质性 DLBCL的研究表明，他们的治疗可以受益于精确医学方法。突变 TLR介体MYD 88和B细胞受体（BCR）信号分子（包括CD 79 B）定义了MCD-1。 DLBCL亚型，表现出最大的侵袭性和对治疗的难治性。myd 88和 BCR前淋巴瘤信号由下游分子复合物整合，其主要功能是 亚基是MALT 1。因此，瞄准MALT 1是专门打断驾驶员的一个有吸引力的选择 这些侵袭性疾病的促淋巴瘤信号并阻止其生长。我们的合作者开发了 第一个选择性MALT 1抑制剂（MALT 1 i），并有助于产生第一个MALT 1 i曾经测试过， 患者（NCT 03900598; NCT 04876092; NCT 04657224）。值得注意的是，MALT 1在抑制细胞增殖的细胞中也很活跃。 - 抗肿瘤免疫，特别是免疫抑制调节性T细胞（TcR）和耗竭的T细胞（Tex）， 它们不能反应并杀死肿瘤细胞。感谢我们对新开发的MCD的独特访问- DLBCL小鼠模型具有完整的免疫系统，我们现在可以第一次可靠地检查 MALT 1 is的直接抗肿瘤和免疫介导的作用，以及它们与 免疫疗法我们在这些模型中的初步研究表明，MALT 1 is减少MCD-DLBCL细胞， 以及淋巴瘤浸润性Tumor和Tex。此外，我们还发现MALT 1可以增加MCD-DLBCL抗原的表达， 呈递和共刺激潜力以及T细胞活化和杀肿瘤功能，这可能 总体上促进抗淋巴瘤T细胞应答。因此，我们假设药理学MALT 1抑制 在MCD-DLBCL的情况下，将具有双重积极的抗肿瘤作用：（1）限制肿瘤增殖， 中断MYD 88和BCR促淋巴瘤信号和（2）增强抗淋巴瘤免疫， 抵消免疫抑制和功能失调的T细胞并增加淋巴瘤细胞免疫原性。 基于这一假设，我们的目标是建立MALT 1 is与免疫治疗的最佳组合， 能够根除其他免疫逃避性侵袭性淋巴瘤。为了实现这一目标，我们将在临床上测试 在同基因小鼠中单独使用相关MALT 1和与针对MCD-DLBCL的免疫疗法联合使用 具有正常与缺陷免疫系统（即缺乏特定T细胞亚群/功能）的模型，以发现 MALT 1抑制促进抗淋巴瘤免疫的机制。此外，我们将执行 首次确认MALT 1 is可激活入组NCT 03900598的患者的T细胞应答。

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.