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Use of Ly6K specific CAR T-cells to treat primary and metastatic triple negative breast cancer

使用 Ly6K 特异性 CAR T 细胞治疗原发性和转移性三阴性乳腺癌

基本信息

批准号：
10112547
负责人：
Geeta Upadhyay
金额：
$ 21.39万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
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：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112547
关键词：
Adverse effects Affect Affinity Binding Biological Markers Blood Blood - brain barrier anatomy Brain Breast Cancer Cell Breast Cancer Model Breast cancer metastasis CD19 gene Cancer Cell Growth Cancer Center Cell Surface Proteins Cell Therapy Cell surface Cells Cessation of life Chimeric Proteins Clinical Trials Colon Carcinoma Data Defect Department of Defense Disease Disease remission Distant Metastasis Ensure Epidermal Growth Factor Receptor Estrogen Receptors Family member Female Future Generations Genes Growth Head Cancer Human Immune Immunotherapy In Vitro Incidence Infertility Knockout Mice Letters Lymphocyte antigen Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Memory Metastatic Neoplasm to the Lung Modeling Monoclonal Antibodies Mus Neck Cancer Neoplasm Metastasis Normal Cell Organ Outcome Patients Progesterone Receptors Prognosis Proteins Proto-Oncogene Proteins c-akt Reproducibility Risk Signal Transduction Solid Spermatogenesis Surface T-Lymphocyte Testing Testis Transforming Growth Factor beta United States Woman Xenograft Model bone cancer cell cancer immunotherapy cancer recurrence cell motility chimeric antigen receptor chimeric antigen receptor T cells cytokine release syndrome effective therapy epithelial to mesenchymal transition experimental study genetically modified cells in vivo innovation knock-down male malignant breast neoplasm malignant stomach neoplasm migration mouse model new therapeutic target novel overexpression research clinical testing side effect sperm cell survival outcome therapeutic target triple-negative invasive breast carcinoma tumor tumor xenograft tumorigenesis vector

项目摘要

Project Summary/abstract We have identified that increased Ly6K expression is associated with poor outcome in triple negative breast cancer (TNBC). Mechanistically, Ly6K is required for the activation of TGFβ signaling and is increased in tumorigenesis in vivo. We propose that the biomarker Ly6K is an ideal therapeutic target for the treatment of TNBC because this protein is not expressed in normal cells, except in testis. Ly6K is also not required for vital organ function, except for spermatogenesis. Thus, targeting this protein for the treatment of TNBC, a disease affecting mostly females, is appropriate and ideal. Because of this, Ly6K is an optimal therapeutic target for TNBC immunotherapy using CAR T-cells. CAR T-cells are genetically modified T cells which express a chimeric antigen receptor fusion protein (CAR) derived from a monoclonal antibody (mAb) recognizing a target protein on the surface of cancer cells. CAR T-cells can recognize and kill target cells expressing the target protein without the need for HLA matching. We have generated three high affinity mAbs against human Ly6K, which recognize the cell surface Ly6K on cancer cells. The sequences from Ly6K mAbs were used to generate a CAR in a third generation lentiviral CAR vector to generate Ly6K-specific CAR T-cells. We will test whether Ly6K-specific CAR T-cells will recognize cancer cells expressing cell surface Ly6K and eliminate them in primary and metastatic TNBC mouse models.

项目概要/摘要我们已经确定Ly 6 K表达增加与三阴性患者预后不良相关，乳腺癌（TNBC）。从机制上讲，Ly 6 K是激活TGFβ信号传导所必需的，并且在TGF β 1/2细胞中增加。体内肿瘤发生。我们认为，生物标志物Ly 6 K是一个理想的治疗靶点，用于治疗 TNBC，因为这种蛋白质在正常细胞中不表达，除了睾丸。Ly 6 K也不需要用于重要的器官功能，除了精子生成。因此，靶向这种蛋白质用于治疗TNBC，主要影响女性，是合适和理想的。正因为如此，Ly 6 K是一个最佳的治疗靶点，使用CAR T细胞的TNBC免疫疗法。CAR T细胞是表达嵌合T细胞的遗传修饰的T细胞。抗原受体融合蛋白（CAR），其衍生自识别靶蛋白的单克隆抗体（mAb），癌细胞的表面。CAR T细胞可以识别并杀死表达靶蛋白的靶细胞，而不需要免疫细胞。需要HLA配型。我们已经产生了三种针对人Ly 6 K的高亲和力mAb，其识别癌细胞表面的Ly 6 K。来自Ly 6 K mAb的序列用于在第三实施方案中产生CAR。在一个实施方案中，所述方法用于产生慢病毒CAR载体以产生Ly 6 K特异性CAR T细胞。我们将测试Ly 6 K特异性CAR T细胞将识别表达细胞表面Ly 6 K的癌细胞，并在原发性和转移性肿瘤中消除它们。 TNBC小鼠模型。