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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.

摘要套细胞淋巴瘤(MCL)占所有非霍奇金淋巴瘤(NHL)的6-8%。虽然数量很大其他NHL的治疗已经取得进展，MCL仍然是一种无法治愈的淋巴瘤，原因是这一点还不清楚。MCL患者预后较差，中位生存期为3-5年。标准护理包括伊布鲁替尼，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。即使是最初的伊布鲁替尼- 敏感患者总是会产生耐药性；然而，伊布鲁替尼耐药的机制现在是安全。由于对DLBCL和CLL中致癌BCR信号的机械性洞察使高效的治疗方法，这项建议将解决致癌BCR的机制- MCL中的信令。在结合全基因组CRISPR-Cas9文库、基因表达谱和BCR信号转导研究，我们发现CEACAM1是一个中心致癌BCR信号的组成部分，在MCL中是必需的，但在正常B细胞或其他B细胞中不是恶性肿瘤。CEACAM1是一种跨膜蛋白，表达于活化的淋巴细胞表面并在其胞质尾部携带两个基于免疫受体酪氨酸的抑制基序(ITIMs)。由于抑制性磷酸酶SHP1在ITIMs中的募集，CEACAM1对T细胞的调节作用受体(TCR)在T细胞中的信号转导，然而，其在正常B细胞和MCL中的功能尚不清楚。出乎意料的是，我们的初步数据显示，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。我们的机械学研究发现CEACAM1将肌动蛋白结合蛋白细丝A募集到质膜上并在抗原结合后激活BCR-近端蛋白激酶Lyn。此外，超级- 分辨共聚焦显微镜显示CEACAM1促进肌动蛋白细胞骨架的重组网络遵循BCR交叉链接。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的CEACAM1嵌合抗原受体(CAR) 人类T细胞。CAR-T细胞在清除CEACAM1+MCL方面具有很高的活性，但缺乏对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信号组件以及 CEACAM1 CAR-T细胞的成功开发，我们假设CEACAM1作为一种是致癌BCR活性的中心驱动力，代表了MCL的一个新的治疗靶点。以下是特定的AIMS将测试和改进基于CEACAM1的MCL疗法的概念：Aim 1)定义 CEACAM1在MCL致癌bcr信号转导中的作用 MCL新的遗传小鼠模型；目的3)靶向CEACAM1的CAR T细胞策略在难治性MCL。拟议研究的结果有望提供：1)关于中央银行的新信息 CEACAM1在致癌BCR信号和MCL中的作用，以及2)新的临床前验证针对难治性MCL中CEACAM1的免疫治疗策略。