Stimulating Neo-Antigen Specific T Cell Responses in Head and Neck Cancers

刺激头颈癌中新抗原特异性 T 细胞反应

基本信息

批准号：
10115173
负责人：
Jorge Silvio Gutkind
金额：
$ 36.6万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
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：
2018-09-18 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115173
关键词：
Address Adoptive Cell Transfers Antigens Autologous Autologous Tumor-Infiltrating Lymphocyte Bioinformatics Cancer Remission Cell Therapy Cells Cellular Immunology Cessation of life Clinical Clonality Combination immunotherapy Complex DNA Sequence Alteration Disease Disease remission Ecosystem Engraftment Epitope spreading Frequencies Gene Expression Profile Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Immune Immune response Immune system Immunotherapeutic agent Lead Malignant Neoplasms Mediating Metadata Methods Modeling Molecular Immunology Mus Mutation Normal tissue morphology Oncogenes Oncology Outcome Patients Peripheral Blood Mononuclear Cell Phenotype Pre-Clinical Model Radiation therapy Radioimmunotherapy Role STING agonists T cell response T-Lymphocyte Testing Tobacco Treatment Efficacy Tumor Burden Tumor Cell Line Tumor-Infiltrating Lymphocytes United States Vaccine Therapy Virus Integration Xenograft procedure adaptive immune response antigen-specific T cells base cancer cell carcinogenesis exome human disease immune checkpoint blockade improved in vivo mouse model neoantigens novel novel therapeutics patient response personalized approach pre-clinical programmed cell death protein 1 receptor response tool transcriptome sequencing tumor tumor xenograft

项目摘要

Abstract Neoantigens (NeoAg) offer a unique and powerful opportunity for directing a patient’s immune response specifically to cancer cells while avoiding damage to normal tissues. Methods for their reliable identification in tumors of moderate mutational burden such as head and neck squamous cell carcinoma (HNSCC) are lacking, however, as are preclinical experimental platforms for utilizing human material to understand the possibilities and impediments in enabling NeoAg-specific T cells to eradicate established tumors. Working with a focused and collaborative team with expertise in cellular and molecular immunology, bioinformatics, and translational oncology, we have developed a set of novel tools and approaches to address the complex tumor/immune ecosystem in new and incisive ways. These include a unique new model of tobacco-induced HNSCC carcinogenesis which recapitulates many key features of the human disease including gene expression patterns of activated oncogenes, a powerful new combined bioinformatic and functional analysis platform the identification of NeoAg by these tumors can be recognized by the host immune system, a novel preclinical model of combination radio-immunotherapy through which NeoAg-specific responses can be induced and sustained (Sharabi/Sharma), and finally, a new preclinical model of tumor-induced unresponsiveness in the setting of adoptive cellular therapy using human HNSCC patient-derived xenograft (PDX) tumors and patient-matched tumor-infiltrating lymphocytes (TIL) specific for an identified NeoAg. Together, these studies will address the hypothesis that autologous NeoAg-specific T cells can eradicate HNSCC tumors as well as defining the key quantitative and qualitative parameters governing therapeutic efficacy.

抽象的新抗原 (NeoAg) 为指导患者的免疫反应提供了独特而强大的机会专门针对癌细胞，同时避免损伤正常组织的方法。缺乏中度突变负荷的肿瘤，例如头颈鳞状细胞癌（HNSCC），然而，利用人体材料来了解可能性的临床前实验平台也是如此以及使 NeoAg 特异性 T 细胞能够消灭已形成的肿瘤的障碍。以及在细胞和分子免疫学、生物信息学和转化方面具有专业知识的协作团队肿瘤学方面，我们开发了一套新颖的工具和方法来解决复杂的肿瘤/免疫问题以新的、深入的方式研究生态系统，其中包括烟草引起的 HNSCC 的独特新模型。致癌作用概括了人类疾病的许多关键特征，包括基因表达模式激活的癌基因，一个强大的新型组合生物信息学和功能分析平台的鉴定这些肿瘤产生的 NeoAg 可以被宿主免疫系统识别，这是一种新的临床前模型联合放射免疫疗法，通过该疗法可以诱导和维持 NeoAg 特异性反应（Sharabi/Sharma），最后，在以下情况下肿瘤引起的无反应的新临床前模型使用人类 HNSCC 患者来源的异种移植 (PDX) 肿瘤和患者匹配的过继细胞疗法这些研究将共同解决对已确定的 NeoAg 具有特异性的肿瘤浸润淋巴细胞 (TIL) 的问题。自体 NeoAg 特异性 T 细胞可以根除 HNSCC 肿瘤的假设并确定了关键控制治疗效果的定量和定性参数。