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

靶向 MALT1 增强抗淋巴瘤免疫力和免疫治疗反应

基本信息

批准号：
10719909
负责人：
Roberta Zappasodi
金额：
$ 47.86万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719909
关键词：
Acceleration Adaptive Immune System Adult Affect Antigen Presentation B-Cell Antigen Receptor B-Cell Lymphomas B-Cell NonHodgkins Lymphoma BCL10 gene Biological Markers Cell Line Cell Survival Cells Chronic Classification Clinic Clinical Clinical Trials Complex Cytostatics Data Defect Disease Engraftment Future Generations Genes Genetic Heterogeneity Genetically Engineered Mouse Goals Growth Heterogeneity Human Immune Immune Evasion Immune system Immunity Immunocompetent Immunodeficient Mouse Immunotherapy In Vitro Infiltration Interruption Large-Cell Lymphomas Lymphoma Lymphoma cell MAPK8 gene Mediating Mediator Modeling Molecular Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mus Mutation New Agents Oncogenic Organoids Pathway interactions Patients Peptide Hydrolases Proliferating Reaction Receptor Signaling Refractory Regimen Regulatory T-Lymphocyte Resistance Resolution Resources Role Sampling Signal Transduction Signal Transduction Pathway Signaling Molecule Specimen T cell response T-Cell Activation T-Cell Lymphoma T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Tumor Escape Tumor Immunity Validation Wild Type Mouse activated B cell like antitumor effect arm biological heterogeneity chimeric antigen receptor T cells clinical development clinical investigation clinically relevant disorder subtype effector T cell exhaust exhaustion first-in-human genetic signature immune checkpoint immune checkpoint blockade immune resistance immunogenicity improved in vivo inhibitor innovation large cell Diffuse non-Hodgkin&apos s lymphoma lymphoid neoplasm mouse model mutant neoplastic cell non-Hodgkin&apos s lymphoma patients novel therapeutics participant enrollment pharmacologic pre-clinical precision medicine programmed cell death ligand 1 resistance mechanism response scaffold secondary lymphoid organ standard care success targeted treatment therapeutic target therapy development therapy resistant transcription factor tumor tumor progression

项目摘要

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.

抽象的弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的 B 细胞非霍奇金淋巴瘤 (B-NHL)。这这些疾病的治疗仍然具有挑战性，许多患者最终死亡。尽管临床尽管最近针对不同肿瘤类型的先进免疫疗法取得了成功，但 DLBCL 在很大程度上难以治愈这些新疗法。这些疾病的免疫抵抗机制尚不清楚。异质性 DLBCL 的研究表明，其治疗可以受益于精准医疗方法。突变在 TLR 介质 MYD88 和 B 细胞受体 (BCR) 信号分子（包括 CD79B）定义了 MCD- DLBCL 亚型，表现出最大的侵袭性和对治疗的难治性。 MYD88 和 BCR 前淋巴瘤信号由下游分子复合物整合，其主要功能亚基是MALT1。因此，以 MALT1 为目标是专门中断驱动程序的一个有吸引力的选择这些侵袭性疾病的前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 MALT1 抑制剂 (MALT1i)，并促成了第一个在患者（NCT03900598；NCT04876092；NCT04657224）。值得注意的是，MALT1 在抑制细胞中的细胞中也很活跃。抗肿瘤免疫，特别是免疫抑制调节性 T 细胞 (Treg) 和耗竭 T 细胞 (Tex)，它们无法反应并杀死肿瘤细胞。得益于我们对新开发的 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 MALT1is 的直接抗肿瘤和免疫介导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 可以减少 MCD-DLBCL 细胞：以及淋巴瘤浸润的 Tregs 和 Tex。此外，我们发现 MALT1 会增加 MCD-DLBCL 抗原呈递和共刺激潜力以及 T 细胞激活和杀肿瘤功能，这可能全面促进抗淋巴瘤 T 细胞反应。因此，我们假设药理 MALT1 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，通过中断 MYD88 和 BCR 前淋巴瘤信号，以及 (2) 增强抗淋巴瘤免疫力，通过对抗免疫抑制和功能失调的 T 细胞，并增加淋巴瘤细胞的免疫原性。基于这一假设，我们的目标是建立 MALT1is 与免疫疗法的最佳组合能够根除免疫逃避侵袭性淋巴瘤。为了这个目标，我们将进行临床测试相关 MALT1 单独使用以及与同系小鼠中针对 MCD-DLBCL 的免疫疗法联合使用具有正常与有缺陷的免疫系统（即缺乏特定 T 细胞子集/功能）的模型，以发现 MALT1 抑制促进抗淋巴瘤免疫的机制。此外，我们将执行首次验证 MALT1is 可以激活参加 NCT03900598 的患者的 T 细胞反应。