Characterization of CEACAM1 as a novel therapeutic in mantle cell lymphoma

CEACAM1 作为套细胞淋巴瘤新疗法的表征

• 批准号: 10059218
• 负责人: VU Nguyen NGO
• 金额: $ 8.23万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059218
• 关键词: Accounting; Affect; Agammaglobulinaemia tyrosine kinase; Alternative Splicing; Antigen Receptors; B lymphoid malignancy; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Biological Process; CEACAM1; CRISPR screen; Cell Line; Clinical Data; Cytoplasmic Tail; Data; Development; Disease; Drug resistance; Epithelial Cells; FDA approved; Future; Gene Expression Profiling; Genes; Genomic approach; Health; Hematopoietic Neoplasms; Human; Hyperactivity; ITIM; Immunotherapeutic agent; Immunotherapy; In Vitro; Integral Membrane Protein; Knowledge; Lead; Leukocytes; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Messenger RNA; Mission; Non-Hodgkin' s Lymphoma; Oncogenic; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphorylation; Play; Prognosis; Protein Isoforms; Proteins; Public Health; Receptor Signaling; Recruitment Activity; Relapse; Research; Resistance; Role; SYK gene; Screening Result; Signal Transduction; Signaling Molecule; T-Lymphocyte; Testing; United States National Institutes of Health; carcinoembryonic antigen-related cell adhesion molecules; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; effective therapy; functional genomics; genome-wide; improved; in vivo; negative affect; novel; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; therapeutic target; tumor

ABSTRACT Mantle cell lymphoma (MCL), accounting for 6-8% of all non-Hodgkin lymphomas (NHLs), is an aggressive and difficult-to-treat B-cell malignancy. MCL patients have a dismal prognosis with a median overall survival of only 3-5 years owing to frequent relapse and resistance to contemporary chemotherapy. Despite recent treatment advances with the FDA-approved drug ibrutinib, which targets the B-cell receptor (BCR) signaling molecule Bruton’s tyrosine kinase (BTK), one-third of MCL patients are ibrutinib-resistant, and even ibrutinib-sensitive patients eventually acquire resistance to the drug. Patients who are insensitive or progress during ibrutinib treatment have very poor outcomes. Thus, more effective post-ibrutinib treatments are urgently needed. Abnormal BCR signaling plays a key oncogenic signal in MCL, but the underlying mechanism is not known. Using an integrated functional genomics approach combining a genome-wide CRISPR-Cas9 screen and gene expression profiling, our group has uncovered CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule-1) as a potential contributor to BCR hyperactivity in MCL. CEACAM1 is a type 1 transmembrane protein expressed as different isoforms due to alternative splicing in epithelial cells and activated leukocytes. In contrast to the short isoform, the CEACAM1 long isoform possesses a cytoplasmic tail that contains the immunoreceptor tyrosine-based inhibitory motif (ITIM) known to negatively regulate the antigen receptor signaling in T cells. We found that CEACAM1 is overexpressed specifically in MCL, as compared to naïve B cells or other B-cell malignancies. Consistent with our CRISPR screen results, depletion of CEACAM1 is toxic in multiple MCL cell lines, but not in non-MCL lymphoma cells. CEACAM1 depletion also markedly reduced proximal BCR signaling (e.g., SYK phosphorylation) and BCR-mediated Ca2+ signaling. More importantly, using T cells that express the CEACAM1-specific chimeric antigen receptor (CAR), we showed that these CAR T cells could effectively eliminate MCL tumors while sparing non-MCL lymphoma in vitro. On the basis of these findings, we hypothesize that CEACAM1 is essential for the oncogenic BCR signaling in MCL and thus a valid therapeutic target for this malignancy. We will test the hypothesis through accomplishing the following specific aims: 1) Determine the mechanisms underlying CEACAM1-regulated BCR signaling; 2) Characterize the MCL-specific expression of CEACAM1; 3) Develop a CAR T-cell strategy to treat MCL in vivo using pre-clinical patient-derived xenograft (PDX) models. Findings from this proposal will improve our limited knowledge of the role of CEACAM1 in MCL pathogenesis. We anticipate that successful completion of the project will provide relevant pre-clinical data for future studies towards developing a novel, effective therapy for MCL.

摘要