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: 10461025
• 负责人: Jorge Silvio Gutkind
• 金额: $ 83.81万
• 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: 2018-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461025
• 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; 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; 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 derived xenograft model; patient response; personalized approach; pre-clinical; programmed cell death protein 1; receptor; response; tool; transcriptome sequencing; translational oncology; 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.

抽象的 新抗原（NeoAg）为指导患者的免疫反应提供了独特而有力的机会 特别针对癌细胞，同时避免对正常组织损害。其可靠识别的方法 缺乏中度突变烧伤的肿瘤，例如头部和颈部鳞状细胞癌（HNSCC），缺乏 但是，以及临床前实验平台，用于利用人类材料了解可能性 并在使NEOAG特异性T细胞降低了肿瘤的障碍中。与专注的 以及具有细胞和分子免疫学，生物信息学和翻译方面的专业知识的合作团队 肿瘤学，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 生态系统以新的和敏锐的方式。这些包括烟草引起的HNSCC的独特新模型 癌变概括了人类疾病的许多关键特征，包括基因表达模式 激活的致癌基因，这是一个强大的新型生物信息学和功能分析平台的识别 这些肿瘤的NEOAG可以通过宿主免疫系统识别，这是一种新型的临床前模型 可以诱导和持续的NEOAG特异性反应的组合免疫疗法 （Sharabi/Sharma），最后是肿瘤引起的新的临床前模型 使用人类HNSCC患者衍生的Xenograpon（PDX）肿瘤和患者匹配的收养细胞疗法 肿瘤浸润淋巴细胞（TIL）针对已鉴定的NEOAG。这些研究将共同​​解决 假设自体NEOAG特异性T细胞可以放射性HNSCC肿瘤并定义钥匙 管理治疗效率的定量和定性参数。

项目成果

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy.

• DOI: 10.1002/jlb.5ri0220-603rr
• 发表时间: 2020-04
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Brightman SE;Naradikian MS;Miller AM;Schoenberger SP
• 通讯作者: Schoenberger SP

Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer.

• DOI: 10.1136/jitc-2021-003821
• 发表时间: 2022-03
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: McCann K;von Witzleben A;Thomas J;Wang C;Wood O;Singh D;Boukas K;Bendjama K;Silvestre N;Nielsen FC;Thomas G;Sanchez-Elsner T;Greenbaum J;Schoenberger S;Peters B;Vijayanand P;Savelyeva N;Ottensmeier C
• 通讯作者: Ottensmeier C