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:
  • 金额:
    $ 36.54万
  • 依托单位:
  • 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

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 世界。据美国疾病控制与预防中心 (CDC) 称,肝癌的发病率在过去 20 年里翻了一番,使其成为全球最严重的癌症。 美国增长最快的癌症。预计新增病例42220例,肝病死亡30200例 2018 年癌症。因此,我们正在解决美国日益严重的健康问题。虽然肝切除术 缺乏辅助治疗成为手术成功的关键障碍,导致~70% 5年复发率。因此,迫切需要新的疗法,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 HCC 的免疫治疗。目前,一款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。我们认为这需要 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 HLA-A2 小鼠中具有多种 TCR 库的 (hAFP) 特异性 CD8 反应。如此大量的CD8细胞 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,我们制定了具有三个具体目标的具体研究策略。 A1:识别 hAFP158 特异性 TCR,用于创建具有不同功能亲和力的 TCR-T; A2:识别 hAFP158 特异性 TCR 没有或有最小的交叉反应性; A3:创建具有干性的可扩展和可拆卸的 TCR-T 达到有效的体内抗肿瘤作用。目标是获得可设计的最佳 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。在 最后,将提交研究性新药和临床试验的申请。这最终将导致新的 HCC 的治疗方法。此外,创建 AFP 特异性 TCR 库的系统方法和 确定具有有效抗肿瘤作用且无毒性的最佳 TCR 可以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。

项目成果

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YUKAI HE其他文献

YUKAI HE的其他文献

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{{ truncateString('YUKAI HE', 18)}}的其他基金

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:
    10063495
  • 财政年份:
    2018
  • 资助金额:
    $ 36.54万
  • 项目类别:
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:
    10331001
  • 财政年份:
    2018
  • 资助金额:
    $ 36.54万
  • 项目类别:
Engineering alpha fetoprotein and glypican-3 to develop hepatoma (HCC) vaccines
改造甲胎蛋白和磷脂酰肌醇蛋白聚糖 3 以开发肝癌 (HCC) 疫苗
  • 批准号:
    8693488
  • 财政年份:
    2014
  • 资助金额:
    $ 36.54万
  • 项目类别:
Engineering alpha fetoprotein and glypican-3 to develop hepatoma (HCC) vaccines
改造甲胎蛋白和磷脂酰肌醇蛋白聚糖 3 以开发肝癌 (HCC) 疫苗
  • 批准号:
    9231438
  • 财政年份:
    2014
  • 资助金额:
    $ 36.54万
  • 项目类别:
Engineering alpha fetoprotein and glypican-3 to develop hepatoma (HCC) vaccines
改造甲胎蛋白和磷脂酰肌醇蛋白聚糖 3 以开发肝癌 (HCC) 疫苗
  • 批准号:
    8827287
  • 财政年份:
    2014
  • 资助金额:
    $ 36.54万
  • 项目类别:
Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization
通过慢载体免疫引发抗肿瘤细胞免疫的机制
  • 批准号:
    7488736
  • 财政年份:
    2007
  • 资助金额:
    $ 36.54万
  • 项目类别:
Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization
通过慢载体免疫引发抗肿瘤细胞免疫的机制
  • 批准号:
    7257540
  • 财政年份:
    2007
  • 资助金额:
    $ 36.54万
  • 项目类别:
Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization
通过慢载体免疫引发抗肿瘤细胞免疫的机制
  • 批准号:
    7759506
  • 财政年份:
    2007
  • 资助金额:
    $ 36.54万
  • 项目类别:
Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization
通过慢载体免疫引发抗肿瘤细胞免疫的机制
  • 批准号:
    7356416
  • 财政年份:
    2007
  • 资助金额:
    $ 36.54万
  • 项目类别:
Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization
通过慢载体免疫引发抗肿瘤细胞免疫的机制
  • 批准号:
    7575681
  • 财政年份:
    2007
  • 资助金额:
    $ 36.54万
  • 项目类别:

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