The role of CEACAM1 in oncogenic B-cell receptor signaling and immunotherapy in mantle cell lymphoma

CEACAM1 在致癌 B 细胞受体信号传导和套细胞淋巴瘤免疫治疗中的作用

• 批准号: 10441539
• 负责人: VU Nguyen NGO
• 金额: $ 39.35万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441539
• 关键词: Actin-Binding Protein; Actins; Activated Lymphocyte; Address; Adhesions; Antibody Therapy; Antigens; Automobile Driving; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; CCND1 gene; CEACAM1; CRISPR library; Cell membrane; Cells; Chronic Lymphocytic Leukemia; Cities; Clinical; Clinical Trials; Collaborations; Confocal Microscopy; Cytoplasmic Tail; Cytoskeleton; Data; Development; Ectopic Expression; Emu species; Engineering; Engraftment; Family; Gene Expression Profiling; Genetic; Human; IGH@ gene cluster; ITIM; Immunoglobulin A; Immunotherapeutic agent; Immunotherapy; In Vitro; Infusion procedures; Integral Membrane Protein; LYN gene; Lymphoma; Lymphoma cell; Mantle Cell Lymphoma; Membrane Microdomains; Molecular; Mus; Mutate; NR0B2 gene; Non-Hodgkin' s Lymphoma; Oncogenic; PTPRC gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphotransferases; Prognosis; Protein Tyrosine Kinase; Receptor Signaling; Refractory; Resistance; Resistance development; Resolution; Role; SOX11 gene; Safety; Signal Pathway; Signal Transduction; Somatic Mutation; Specificity; Surface; Survival Analysis; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Validation; Xenograft procedure; alpha Actin; base; cell type; chimeric antigen receptor; chimeric antigen receptor T cells; crosslink; design; effective therapy; efficacy testing; experimental study; filamin; genome-wide; immunoglobulin B; improved; in vivo; in vivo Model; insight; large cell Diffuse non-Hodgkin' s lymphoma; medical schools; mouse model; new therapeutic target; novel; overexpression; pre-clinical; preclinical evaluation; recruit; safety testing; small molecule inhibitor; standard of care; therapeutic target; therapeutically effective; tumor

Abstract Mantle cell lymphoma (MCL) accounts for 6-8% of all non-Hodgkin lymphomas (NHLs). While substantial therapeutic advances have been achieved for other NHLs, MCL remains an incurable lymphoma, the reason of which is not known. MCL patients have a dismal prognosis with a median overall survival of 3-5 years. Standard of care includes ibrutinib, a small molecule inhibitor of the B-cell receptor (BCR)-proximal tyrosine kinase BTK. However, one-third of MCL patients do not respond to the drug. Even initially ibrutinib- sensitive patients invariably develop resistance; however, the mechanisms of ibrutinib-resistance are now clear. Since mechanistic insight into oncogenic BCR signaling in DLBCL and CLL enabled the development of highly effective treatment approaches, this proposal will address the mechanisms of oncogenic BCR- signaling in MCL. In an integrated functional analysis combining a genome-wide CRISPR-Cas9 library, gene expression profiling and BCR signal transduction studies, we have uncovered CEACAM1 as a central component of oncogenic BCR signaling that is essential in MCL but not in normal B cells or other B-cell malignancies. As a transmembrane protein, CEACAM1 is expressed on the surface of activated lymphocytes and carries two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on its cytoplasmic tail. Owing to recruitment of the inhibitory phosphatase SHP1 to the ITIMs, CEACAM1 functions as a regulator of T-cell receptor (TCR) signaling in T cells, however, its function in normal B cells and MCL is not known. Unexpectedly, our preliminary data showed that CEACAM1 function induced a net increase of BCR signaling, leading to increased survival and proliferation of MCL cells in vitro and in vivo. Our mechanistic studies revealed that CEACAM1 recruited the actin-binding protein filamin A to the plasma membrane microdomains and activated the BCR-proximal kinase LYN after antigen engagement. Furthermore, super- resolution confocal microscopy revealed that CEACAM1 promoted reorganization of the actin cytoskeletal network following BCR cross-linking. Leveraging the clinical grade Cell Therapeutics Facility at City of Hope, we designed and validated a novel CEACAM1 chimeric antigen receptor (CAR) engineered in primary human T cells. The CAR-T cells were highly active in eliminating CEACAM1+ MCL but lacked reactivity against other cell types. Based on our discovery of CEACAM1 as a critical BCR signaling component in MCL and the successful development of CEACAM1 CAR-T cells, we hypothesize that CEACAM1 functions as a central driver of oncogenic BCR activity and represents a novel therapeutic target in MCL. The following specific aims will test and refine the concept of CEACAM1-based therapies for MCL: Aim 1) Define the mechanistic role of CEACAM1 in oncogenic BCR signaling in MCL; Aim 2) Dissect the role of CEACAM1 in new genetic mouse models for MCL; Aim 3) Validation of CAR T-cell strategies targeting CEACAM1 in refractory MCL. Results from the proposed studies are expected to provide: 1) new information on the central role of CEACAM1 in oncogenic BCR signaling and MCL, and 2) pre-clinical validation of novel immunotherapeutic strategies targeting CEACAM1 in refractory MCL.

抽象的 地幔细胞淋巴瘤（MCL）占所有非霍奇金淋巴瘤（NHLS）的6-8％。虽然很大 对于其他NHL，MCL仍然无法治愈，这是无法治愈的淋巴瘤，这是 这是不知道的。 MCL患者的预后较弱，总体存活率中位数为3 - 5年。 护理标准包括ibrutinib，ibrutinib是B细胞受体（BCR） - 羟基酪氨酸的小分子抑制剂 激酶BTK。但是，三分之一的MCL患者对该药物没有反应。甚至最初是ibrutinib- 敏感的患者总是会产生抗药性。但是，现在的耐瑞替尼的机制是 清除。由于DLBCL中对致癌BCR信号传导的机械洞察力，并使CLL得以发展 高效的治疗方法，该建议将解决致癌BCR-的机制 在MCL中发出信号。在结合全基因组CRISPR-CAS9库的集成功能分析中，基因 表达分析和BCR信号转导研究，我们发现了CEACAM1作为中央 在MCL中必不可少的，但在正常B细胞​​或其他B细胞中不必要的致癌BCR信号的成分 恶性肿瘤。作为跨膜蛋白，CEACAM1在活化的淋巴细胞表面表达 并在其细胞质尾部携带两个免疫受体酪氨酸抑制基序（ITIMS）。由于 将抑制性磷酸酶SHP1募集到ITIMS，CEACAM1作为T细胞的调节剂 然而，T细胞中的受体（TCR）信号传导在正常B细胞​​和MCL中的功能尚不清楚。 出乎意料的是，我们的初步数据表明，CEACAM1函数诱导BCR信号的净增加，即 导致MCL细胞在体外和体内的生存和增殖增加。我们的机械研究 发现CEACAM1募集了肌动蛋白结合蛋白丝蛋白A到质膜 微域并激活了抗原参与后的BCR-羟基激酶Lyn。此外，超级 分辨率共聚焦显微镜表明，CEACAM1促进了肌动蛋白细胞骨架的重组 BCR交联后的网络。利用希望城市的临床级细胞治疗设施 我们设计并验证了一种新型的CeCAM1嵌合抗原受体（CAR） 人类T细胞。 CAR-T细胞在消除CEACAM1+ MCL方面高度活跃，但缺乏反应性 其他细胞类型。基于我们发现CEACAM1作为MCL和MCL中的关键BCR信号分量 CEACAM1 CAR-T细胞的成功开发，我们假设CEACAM1充当 致癌性BCR活性的中心驱动力，代表了MCL中新型的治疗靶点。下列 具体目的将测试和完善基于CEACAM1的MCL疗法的概念：AIM 1）定义 CEACAM1在MCL中的致癌BCR信号传导中的机械作用；目标2）剖析CECAM1在 MCL的新遗传小鼠模型；目标3）验证针对CEACAM1的汽车T细胞策略 难治性MCL。预计拟议研究的结果将提供：1）中央有关的新信息 CEACAM1在致癌BCR信号和MCL中的作用，以及2）新颖的临床前验证 针对难治性MCL中CEACAM1的免疫治疗策略。