TCR engineering of human T cells for immunotherapy of hepatocellular carcinoma

人类 T 细胞的 TCR 工程用于肝细胞癌的免疫治疗

基本信息

批准号：
10063495
负责人：
YUKAI HE
金额：
$ 2.99万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-07 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063495
关键词：
AFP gene Address Adjuvant Therapy Adult Affinity Allogenic Antigens Autologous Autologous Dendritic Cells Avidity Binding CD8 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Cetuximab Chimeric Proteins Clinical Trials Clone Cells Data Dendritic Cells Disease Engineering Epidermal Growth Factor Receptor Epitopes Excision FDA approved Future Goals HLA-A2 Antigen Haplotypes Health HepG2 Hepatocyte Human Human Engineering Hybridomas Immunization Immunotherapy In Vitro Incidence Interleukin-15 Lead Lesion Libraries Light Liver Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Memory Methods Mus Normal Cell Normal tissue morphology Operative Surgical Procedures Patients Peptides Pharmaceutical Preparations Physiologic pulse Primary carcinoma of the liver cells Process Protocols documentation Recurrence Research Safety Scanning Signal Transduction Specificity System T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte T-cell receptor repertoire Testing Tissues Toxic effect Transgenic Organisms Tumor Tissue Vaccines Xenograft Model alpha-Fetoproteins antitumor effect cross reactivity cytotoxicity effective therapy hepatocellular carcinoma cell line in vivo man neoplasm immunotherapy neoplastic cell novel therapeutic intervention novel therapeutics patient derived xenograft model response safety study single cell sequencing stem stemness success tumor

项目摘要

Project Summary Liver cancer is the 6th most common cancer and the 4th most common cause of cancer death in the world. According to CDC, the incidence rate of liver cancer has doubled over last 20 years, making it the fastest growing cancer in US. It is estimated that there will be 42,220 new cases and 30,200 death of liver cancer in 2018. Thus, we are addressing an increasing health problem in US. Although liver resection is curative, the lack of adjuvant therapy becomes a critical barrier to the success of surgery, resulting in ~70% 5yr recurrence rate. Thus, novel therapies are urgently needed and immunotherapy has a great potential. Majority (80-90%) of liver cancer is hepatocellular carcinoma (HCC), which re-express alpha fetoprotein (AFP). Engineering patient’s autologous T cells with AFP epitope-specific T cell receptor (TCR) genes offers a specific immunotherapy for HCC. Currently, one AFP158-specific high-affinity TCR just got approved for clinical trial in May of 2017. But, high-affinity TCRs may cause severe on- and off-target toxicity. We reason that it will require a panel of TCRs with different affinity to find the optimal TCRs that enable human T cells to kill HCC tumor cells without toxicity. Thus, we propose to identify multiple AFP-specific TCRs and test their antitumor efficacy and toxicity. We hypothesize that an effective in vivo immunization strategy will induce potent human AFP (hAFP)-specific CD8 response with diverse TCR repertoire in HLA-A2 mice. This large number of CD8 cells enables us to directly study their antitumor function and identify a panel of TCRs with different affinity, increasing the chance of finding the optimal TCRs to create TCR-Ts of potent antitumor effect without toxicity. To test this hypothesis, we have developed a concrete research strategy with three specific aims. A1: Identify hAFP158-specific TCRs to create TCR-Ts of different functional avidity; A2: Identify the hAFP158-specific TCRs without or with minimal cross-reactivity; and A3: Create expandable and removable TCR-Ts with stemness to achieve potent in vivo antitumor effect. The goals are to obtain the optimal TCR genes that can engineer primary human T cells to become effective TCR-Ts capable of killing human HCC cells without harming normal cells and to establish protocol for generating safe and effective TCR-Ts that are ready for clinical trials. In the end, applications for an investigative new drug and clinical trial will be filed. This will eventually lead to new therapeutic approach for HCC. In addition, the methodical approach of creating AFP-specific TCR library and identifying optimal TCRs with potent antitumor effect and no toxicity will serve as a platform for other antigens and HLA haplotypes, which will greatly impact the field of tumor immunotherapy.

项目摘要肝癌是第六个最常见的癌症，也是癌症死亡的第四最常见原因世界。根据CDC的数据，肝癌的事件率在过去20年中增加了一倍，使其成为在美国增长最快的癌症。据估计，将有42,220例新病例和30,200例肝脏死亡 2018年的癌症。那我们正在解决我们越来越多的健康问题。虽然肝切除是治愈性，缺乏适应疗法成为手术成功的关键障碍，导致约70％ 5年复发率。这是迫切需要新颖的疗法，免疫疗法具有很大的潜力。大多数（80-90％）的肝癌是肝细胞癌（HCC），它重新表达了α胎儿蛋白（AFP）。具有AFP表位特异性T细胞受体（TCR）基因的工程患者的自体T细胞提供了特定 HCC的免疫疗法。目前，一个AFP158特异性的高亲和力TCR刚刚获得了临床试验的批准 2017年5月。但是，高亲和力的TCR可能会引起严重的靶向和脱靶毒性。我们认为这需要具有不同亲和力的TCR面板，以找到使人T细胞杀死HCC肿瘤的最佳TCR 细胞没有毒性。这是我们建议识别多个AFP特异性TCR并测试其抗肿瘤效率和毒性。我们假设有效的体内免疫刺激策略将引起有效的人类AFP （HAFP）在HLA-A2小鼠中对潜水员TCR库的特异性CD8响应。大量的CD8细胞使我们能够直接研究其抗肿瘤功能，并确定具有不同亲和力的TCR小组增加找到最佳TCR的机会创建潜在抗肿瘤效应的TCR-TS而没有毒性。为了检验这一假设，我们制定了一种具体的研究策略，具有三个特定的目标。 A1：识别 hafp158特异性TCR可创建不同功能性感的TCR-TS； A2：识别HAFP158特异性TCR 没有或没有最小的交叉反应性；和A3：创建可扩展和可移动的TCR-TS，并实现潜在的体内抗肿瘤效应。目标是获得可以设计的最佳TCR基因原代人T细胞成为有效的TCR-TS，能够杀死人类HCC细胞而不会损害正常细胞并建立用于生成准备临床试验的安全有效的TCR-TS的方案。在最后，将提出调查性新药和临床试验的申请。这最终将导致新 HCC的治疗方法。此外，创建AFP特异性TCR库和鉴定具有潜在抗肿瘤效应和无毒性的最佳TCR将作为其他抗原的平台 HLA单倍型将极大地影响肿瘤免疫疗法领域。