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

• 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
• 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

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.

摘要 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 特别是癌细胞，同时避免对正常组织的损害。可靠的鉴定方法 缺乏中等突变负荷的肿瘤如头颈部鳞状细胞癌（HNSCC）， 然而，正如临床前实验平台一样，利用人体材料来了解可能性， 以及阻碍NeoAg特异性T细胞根除已建立的肿瘤。与专注的 在细胞和分子免疫学、生物信息学和翻译方面具有专业知识的团队 肿瘤学，我们已经开发了一套新的工具和方法来解决复杂的肿瘤/免疫 生态系统以新的和深刻的方式。其中包括烟草诱导的HNSCC的独特新模型 癌症的发生，它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，一个强大的新的生物信息学和功能分析平台， 这些肿瘤的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特异性应答 （Sharabi/Sharma），最后，一种新的肿瘤诱导的无反应性的临床前模型， 使用人HNSCC患者来源的异种移植（PDX）肿瘤和患者匹配的 肿瘤浸润淋巴细胞（TIL），其对所鉴定的NeoAg具有特异性。这些研究将共同解决 假设自体NeoAg特异性T细胞可以根除HNSCC肿瘤，并定义了 控制治疗效果的定量和定性参数。