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

• 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
• 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

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 肝癌是世界上第六大最常见的癌症，也是第四大最常见的癌症死亡原因。 世界根据CDC的数据，肝癌的发病率在过去20年中翻了一番，使其成为世界上最严重的癌症。 美国癌症增长最快原标题：预计新增42,220例肝源性死亡30,200例 2018年的癌症因此，我们正在解决美国日益严重的健康问题。虽然肝切除是 在治愈性方面，缺乏辅助治疗成为手术成功的关键障碍，导致约70% 5年复发率。因此，迫切需要新的治疗方法，免疫治疗具有很大的潜力。 大多数（80-90%）肝癌是肝细胞癌（HCC），其再表达甲胎蛋白（AFP）。 用AFP表位特异性T细胞受体（TCR）基因工程化患者的自体T细胞提供了特异性免疫应答。 免疫治疗HCC。目前，一种AFP 158特异性高亲和力TCR刚刚获得批准用于临床试验。 2017年5月但是，高亲和力TCR可能导致严重的靶向和脱靶毒性。我们推断这需要 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 细胞无毒性。因此，我们建议鉴定多种AFP特异性TCR并测试其抗肿瘤功效 和毒性。我们假设有效的体内免疫策略将诱导有效的人AFP 在HLA-A2小鼠中用不同的TCR库检测（hAFP）特异性CD 8应答。大量的CD 8细胞 使我们能够直接研究它们的抗肿瘤功能并识别一组具有不同亲和力的TCR， 增加了找到最佳TCR的机会，以产生无毒性的有效抗肿瘤作用的TCR-T。 为了验证这一假设，我们制定了一个具体的研究策略，有三个具体的目标。A1：识别 A2：鉴定hAFP 158特异性TCR，以产生不同功能亲合力的TCR-T; A3：产生可扩展和可移除的TCR-T，具有干细胞性， 具有较强的体内抗肿瘤作用。我们的目标是获得最佳的TCR基因， 原代人T细胞成为有效的TCR-T细胞，能够杀死人HCC细胞，而不损害正常 细胞，并建立用于产生准备用于临床试验的安全有效的TCR-T的方案。在 最后，申请研究性新药和临床试验。这将最终导致新的 HCC的治疗方法。此外，还介绍了建立AFP特异性TCR文库的方法， 鉴定具有有效抗肿瘤作用且无毒性的最佳TCR将作为其它抗原的平台 和HLA单倍型，这将极大地影响肿瘤免疫治疗领域。