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：
10331001
负责人：
YUKAI HE
金额：
$ 36.54万
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/10331001
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 vaccination strategy

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.

项目概要肝癌是全球第六大常见癌症，也是第四大癌症死亡原因据美国疾病控制与预防中心 (CDC) 统计，过去 20 年来，肝癌的发病率翻了一番，成为全球癌症发病率最高的癌症。美国增长最快的癌症预计将有 42,220 例新发癌症病例和 30,200 例肝癌死亡病例。 2018 年癌症。因此，我们正在解决美国日益严重的健康问题，尽管肝切除术是一种治疗方法。缺乏辅助治疗成为手术成功的关键障碍，导致~70% 因此，迫切需要新的疗法，并且免疫疗法具有巨大的潜力。大多数（80-90%）肝癌是肝细胞癌（HCC），其重新表达甲胎蛋白（AFP）。将患者的自体 T 细胞与 AFP 表位特异性 T 细胞受体 (TCR) 基因进行工程改造，可提供特定的目前，一种AFP158特异性高亲和力TCR刚刚在中国获批进入临床试验。 2017 年 5 月。但是，高亲和力 TCR 可能会导致严重的靶向和脱靶毒性。一组具有不同亲和力的TCR，以找到使人类T细胞能够杀死HCC肿瘤的最佳TCR 因此，我们建议鉴定多种 AFP 特异性 TCR 并测试其抗肿瘤功效。我们认为有效的体内免疫策略将诱导有效的人 AFP。 HLA-A2 小鼠中具有多种 TCR 库的 (hAFP) 特异性 CD8 反应。使我们能够直接研究它们的抗肿瘤功能并鉴定一组具有不同亲和力的TCR，增加找到最佳 TCR 的机会，以创建具有有效抗肿瘤作用且无毒性的 TCR-T。为了检验这一假设，我们制定了一项具体的研究策略，具有三个具体目标 A1：确定。 hAFP158 特异性 TCR，用于创建不同功能亲和力的 TCR-T；A2：识别 hAFP158 特异性 TCR；没有或很少有交叉反应性；以及 A3：创建具有干性的可扩展和可拆卸的 TCR-T 实现有效的体内抗肿瘤作用，目标是获得可改造的最佳TCR基因。原代人类 T 细胞成为有效的 TCR-T，能够杀死人类 HCC 细胞而不损害正常细胞细胞并建立生成安全有效的 TCR-T 的方案，为临床试验做好准备。最后，将提交研究性新药和临床试验的申请，这最终将导致新药的出现。此外，创建 AFP 特异性 TCR 库的方法和方法。具有有效抗肿瘤作用且无毒性的最佳 TCR 将作为其他抗原的平台和HLA单倍型，这将极大地影响肿瘤免疫治疗领域。