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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

基本信息

批准号：
10662578
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
项目类别：
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/10662578
关键词：
Actin-Binding Protein Actins Activated Lymphocyte 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 Survival Cell membrane Cells Chronic Lymphocytic Leukemia Cities Clinical Clinical Trials Collaborations Confocal Microscopy Cytoplasmic Tail Cytoskeleton Data Development Ectopic Expression Engineering Engraftment Experimental Genetics 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 Membrane Microdomains Molecular Mus Mutate NR0B2 gene Non-Hodgkin&apos s Lymphoma Oncogenic PTPRC gene Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphotransferases Prognosis Proliferating Protein Tyrosine Kinase Receptor Signaling Refractory Resistance Resistance development 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 cell type chimeric antigen receptor chimeric antigen receptor T cells crosslink design effective therapy efficacy testing filamin genome-wide immunoglobulin B improved in vivo in vivo Model insight large cell Diffuse non-Hodgkin&apos 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 ultra high resolution

项目摘要

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.

抽象的套细胞淋巴瘤 (MCL) 占所有非霍奇金淋巴瘤 (NHL) 的 6-8%。虽然实质性其他 NHL 的治疗已取得进展，但 MCL 仍然是一种无法治愈的淋巴瘤，这是这是未知的。 MCL 患者预后不佳，中位总生存期为 3-5 年。标准护理包括依鲁替尼，一种 B 细胞受体 (BCR) 近端酪氨酸的小分子抑制剂激酶 BTK。然而，三分之一的 MCL 患者对该药物没有反应。即使最初伊布替尼- 敏感的患者总是会产生耐药性；然而，目前对依鲁替尼耐药的机制清除。由于对 DLBCL 和 CLL 中致癌 BCR 信号传导的机制深入了解，使得开发高效的治疗方法，该提案将解决致癌 BCR- 的机制 MCL 中的信号传导。在结合全基因组 CRISPR-Cas9 文库的综合功能分析中，基因通过表达谱分析和 BCR 信号转导研究，我们发现 CEACAM1 作为一个核心致癌 BCR 信号传导的组成部分，在 MCL 中至关重要，但在正常 B 细胞或其他 B 细胞中则不然恶性肿瘤。 CEACAM1 作为一种跨膜蛋白，表达于活化的淋巴细胞表面并在其细胞质尾部携带两个基于免疫受体酪氨酸的抑制基序（ITIM）。由于将抑制性磷酸酶 SHP1 招募到 ITIM，CEACAM1 充当 T 细胞的调节器 T 细胞中的受体 (TCR) 信号传导，但其在正常 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 功能诱导了 BCR 信号的净增加，导致 MCL 细胞在体外和体内的存活和增殖增加。我们的机制研究揭示 CEACAM1 将肌动蛋白结合蛋白 filamin A 募集至质膜微结构域并在抗原结合后激活 BCR 近端激酶 LYN。此外，超分辨率共聚焦显微镜显示 CEACAM1 促进肌动蛋白细胞骨架的重组 BCR 交联后的网络。利用希望之城的临床级细胞治疗设施，我们设计并验证了一种新型 CEACAM1 嵌合抗原受体 (CAR)，该受体经过原代工程改造人类 T 细胞。 CAR-T 细胞在消除 CEACAM1+ MCL 方面高度活跃，但缺乏针对 CEACAM1+ MCL 的反应性。其他细胞类型。基于我们发现 CEACAM1 作为 MCL 中关键的 BCR 信号传导成分以及随着 CEACAM1 CAR-T 细胞的成功开发，我们假设 CEACAM1 的功能是作为致癌 BCR 活性的核心驱动因素，代表了 MCL 的新治疗靶点。下列具体目标将测试和完善基于 CEACAM1 的 MCL 疗法的概念：目标 1) 定义 CEACAM1 在 MCL 致癌 BCR 信号传导中的机制作用；目标 2) 剖析 CEACAM1 在 MCL 的新基因小鼠模型；目标 3) 验证针对 CEACAM1 的 CAR T 细胞策略难治性 MCL。拟议研究的结果预计将提供：1）关于中央的新信息 CEACAM1 在致癌 BCR 信号传导和 MCL 中的作用，以及 2) 新型药物的临床前验证针对难治性 MCL 中 CEACAM1 的免疫治疗策略。