Head & Neck Cancer Neoantigen Characterization & Therapeutic Targeting

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基本信息

批准号：
10180937
负责人：
SEBASTIAN JOYCE
金额：
$ 45.54万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180937
关键词：
Adjuvant Algorithms Antigens Antitumor Response Autologous Bioinformatics Cancer Patient Cancer Vaccines Cells Chronic Clinical Clinical Trials Data Development Epitope spreading Epitopes Formulation Future Goals HLA-A2 Antigen Head Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Human Human Papillomavirus Immune checkpoint inhibitor Immunologics Immunotherapeutic agent Interferons Longitudinal cohort MHC Class I Genes Malignant neoplasm of larynx Maps Mass Spectrum Analysis Metastatic/Recurrent Methods Mission Modality Modeling Mus Mutation National Institute of Dental and Craniofacial Research Neck Cancer Neoadjuvant Therapy Nivolumab Operative Surgical Procedures Oral health Patients Peptides Proteomics STING agonists Specimen System T cell response T-Lymphocyte Testing Therapeutic Agents United States National Institutes of Health Vaccines base cancer immunotherapy cancer therapy cancer type checkpoint therapy clinical translation combinatorial exome sequencing experimental study head and neck cancer patient humanized mouse improved in silico in vivo in vivo Model malignant mouth neoplasm malignant oropharynx neoplasm mouse model multiple reaction monitoring nanoparticle nanoparticle delivery neoantigens neoplastic cell novel novel strategies patient derived xenograft model personalized immunotherapy pre-clinical prediction algorithm response response biomarker single cell sequencing targeted treatment therapeutic target tobacco exposure transcriptome sequencing translational impact tumor tumor immunology whole genome

项目摘要

Project Summary Head & neck squamous cell carcinoma (HNSCC) is currently showing clinical response to immune checkpoint inhibitors, but its efficacy is still low at nearly 20% of the recurrent/metastatic patients treated. One immunological strategy to improve upon this low efficacy rate is to target the high mutational burden of HNSCC, particularly those associated with chronic tobacco exposure. We propose to characterize the mutation associated neoantigen landscape of human HNSCC obtained from patients treated with nivolumab in a neoadjuvant setting using both in silico and mass spectroscopy methods to directly obtain these human neo- epitopes. In conjunction with these studies, we will characterize the immunodominant MHC restricted neoantigens in an autologous humanized murine system in vivo. These findings will help direct a novel strategy to expand these neoantigen-specific T-cells using a potent STING agonist formulated nanoparticles with known neoantigens found in human HNSCC. Findings from this proposal will also impact how neoantigen-based cancer vaccines should be administered in conjunction with immune checkpoint inhibitors in future head and neck clinical trials. Lastly, our proposal will also inform neoepitope prediction algorithms and antigen based trials for other cancer types to have deep impact in the field of cancer immunology as a whole.

项目概要头颈鳞状细胞癌 (HNSCC) 目前显示出临床反应免疫检查点抑制剂，但其疗效仍然较低，接近20% 接受治疗的复发/转移患者。一种改善这种低水平的免疫策略有效率是针对 HNSCC 的高突变负荷，特别是那些相关的长期接触烟草。我们建议表征突变相关的新抗原从接受新辅助纳武单抗治疗的患者获得的人类 HNSCC 的景观设置使用计算机和质谱方法直接获得这些人类新表位。结合这些研究，我们将描述免疫显性 MHC 体内自体人源化小鼠系统中的限制性新抗原。这些发现将帮助指导一种新策略，使用有效的 STING 来扩增这些新抗原特异性 T 细胞激动剂配制的纳米颗粒与人类 HNSCC 中发现的已知新抗原。发现该提案还将影响基于新抗原的癌症疫苗的研发方式在未来的头颈临床中与免疫检查点抑制剂联合给药试验。最后，我们的建议还将为新表位预测算法和基于抗原的算法提供信息其他癌症类型的试验对整个癌症免疫学领域产生深远影响。