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.

摘要