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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：
10532224
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/10532224
关键词：
Address Adjuvant Therapy Adult Affinity Allogenic Antigens Autologous Autologous Dendritic Cells Avidity Binding CD8 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cells Cessation of life Cetuximab Chimeric Proteins Clinical Trials Clone Cells Cross Reactions 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 Lesion Libraries Light Liver Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Memory Methods Mus Normal Cell Normal tissue morphology Operative Surgical Procedures PIK3CG gene 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 clinical trial readiness 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.

项目总结