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细胞性非霍奇金淋巴瘤(B-NHL)。这个 这些疾病的治疗仍然具有挑战性，许多患者最终会死亡。尽管临床上 最近针对不同肿瘤类型的先进免疫疗法的成功，DLBCL在很大程度上对 这些新疗法。这些疾病的免疫耐药机制尚不清楚。异质性 DLBCL的研究表明，他们的治疗可以从精确医学方法中受益。基因突变 TLR介体MYD88和B细胞受体(BCR)信号分子，包括CD79B，定义了MCD- DLBCL亚型，对治疗表现出最大的侵袭性和耐受性。MyD88和 BCR前淋巴瘤信号被下游的分子复合体整合，其主要功能是 亚基为MALT1。因此，以MALT1为目标是专门中断驾驶员的一个有吸引力的选择 原淋巴瘤是这些侵袭性疾病的信号，并阻止它们的生长。我们的合作者开发了 第一个选择性MALT1抑制剂(MALT1i)，并促成了有史以来测试的第一个MALT1i的产生 患者(NCT03900598；NCT04876092；NCT04657224)。值得注意的是，MALT1在抑制的细胞中也是活跃的 抗肿瘤免疫，特别是免疫抑制调节性T细胞(Tregs)和耗竭T细胞(TeX)； 它们不能反应并杀死肿瘤细胞。感谢我们独一无二地接触到新开发的MCD- 拥有完整免疫系统的DLBCL小鼠模型，我们现在可以第一次可靠地检查 MALT1的直接抗肿瘤和免疫调节作用及其与 免疫疗法。我们在这些模型中的初步研究表明，MALT1使MCD-DLBCL细胞减少为 以及淋巴瘤浸润性Tregs和Tex。此外，我们还发现MALT1增加了MCD-DLBCL抗原 呈递和共刺激潜力以及T细胞激活和杀瘤功能，这可能 全面促进抗淋巴瘤T细胞应答。因此，我们假设药物对MALT1的抑制 在MCD-DLBCL的背景下，将具有双重积极的抗肿瘤作用：(1)限制肿瘤增殖，通过 阻断MYD88和BCR前淋巴瘤信号和(2)增强抗淋巴瘤免疫，通过 对抗免疫抑制和功能失调的T细胞，提高淋巴瘤细胞的免疫原性。 基于这一假设，我们的目标是建立MALT1与免疫疗法的最佳组合 能够根除原本免疫的逃避性侵袭性淋巴瘤。为了实现这一目标，我们将进行临床试验。 相关MALT1单独及联合免疫治疗对同基因小鼠MCD-DLBCLs的影响 免疫系统正常与缺陷(即缺乏特定T细胞亚群/功能)的模型 抑制MALT1促进抗淋巴瘤免疫的机制。此外，我们还将执行 首次验证MALT1IS可以激活NCT03900598登记患者的T细胞反应。

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.