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

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 专门针对癌细胞，同时避免对正常组织造成损害。其可靠识别方法 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 NeoAg 特异性 T 细胞根除既定肿瘤的障碍。与专注的人一起工作 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、深入的方式构建生态系统。其中包括烟草诱发的 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 对已确定的 NeoAg 具有特异性的肿瘤浸润淋巴细胞 (TIL)。这些研究将共同解决 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。

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.