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
- 来源:
- 关键词:AddressAdjuvant TherapyAdultAffinityAllogenicAntigensAutologousAutologous Dendritic CellsAvidityBindingCD8 AntigensCD8-Positive T-LymphocytesCD8B1 geneCancer EtiologyCellsCessation of lifeCetuximabChimeric ProteinsClinical TrialsClone CellsCross ReactionsDataDendritic CellsDiseaseEngineeringEpidermal Growth Factor ReceptorEpitopesExcisionFDA approvedFutureGoalsHLA-A2 AntigenHaplotypesHealthHepG2HepatocyteHumanHuman EngineeringHybridomasImmunizationImmunotherapyIn VitroIncidenceInterleukin-15LesionLibrariesLightLiverMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of liverMemoryMethodsMusNormal CellNormal tissue morphologyOperative Surgical ProceduresPIK3CG genePatientsPeptidesPharmaceutical PreparationsPhysiologic pulsePrimary carcinoma of the liver cellsProcessProtocols documentationRecurrenceResearchSafetyScanningSignal TransductionSpecificitySystemT-Cell ActivationT-Cell ProliferationT-Cell ReceptorT-Cell Receptor GenesT-LymphocyteT-cell receptor repertoireTestingTissuesToxic effectTransgenic OrganismsTumor TissueVaccinesXenograft Modelalpha-Fetoproteinsantitumor effectclinical trial readinesscross reactivitycytotoxicityeffective therapyhepatocellular carcinoma cell linein vivomanneoplasm immunotherapyneoplastic cellnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelresponsesafety studysingle cell sequencingstemstemnesssuccesstumorvaccination 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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