Immunotherapeutic responses to neoantigens in head and neck cancer

头颈癌对新抗原的免疫治疗反应

基本信息

批准号：
9888974
负责人：
Ravindra Uppaluri
金额：
$ 57.8万
依托单位：
DANA-FARBER CANCER INST
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：
2018-04-11 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888974
关键词：
Address American Society of Clinical Oncology Antigens Biological Markers Biology CD8-Positive T-Lymphocytes Carcinogens Caring Cell Line Cisplatin Clinical Clinical Trials Combined Modality Therapy Coupled Coupling Data Distant Metastasis Dose Foundations Genomics Goals HPV-High Risk Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human ICAM1 gene Immune Immune Targeting Immune checkpoint inhibitor Immune response Immune system Immunobiology Immunocompetent Immunogenomics Immunophenotyping Immunotherapeutic agent Immunotherapy In complete remission Knowledge Laboratories Malignant Neoplasms Mediating Metastatic Neoplasm to Lymph Nodes Metastatic/Recurrent Methodology Modeling Mouth Carcinoma Mus Mutate Mutation National Institute of Dental and Craniofacial Research Neoadjuvant Therapy Nivolumab Non-Small-Cell Lung Carcinoma Oncology Operative Surgical Procedures Outcome Pathologic Pathology Patient Care Patients Pattern Phase Primary Neoplasm Recurrence Recurrent disease Reporting Resectable Resistance Sampling Specimen T cell response T-Cell Activation T-Lymphocyte T-cell inflamed Technology Therapeutic Translating Transplantation Treatment Efficacy Treatment Failure Tumor Antigens Vaccination Work anti-PD-1 anti-PD1 antibodies anti-PD1 therapy antigen-specific T cells base cancer cell draining lymph node experimental study genomic data immune checkpoint blockade improved in vivo insight melanoma mouse model mouth squamous cell carcinoma multidisciplinary neoantigen vaccination neoantigen vaccine neoantigens novel programs prospective response screening single-cell RNA sequencing therapeutic target transcriptome transcriptome sequencing transcriptomics translational study treatment responders tumor tumor growth

项目摘要

PROJECT SUMMARY In this application, we have assembled a multidisciplinary team to execute an integrated mechanistic and translational program to defining neoantigen biology in head and neck squamous cell carcinomas (HNSCC). Despite advances in multimodality treatment, a significant number of HNSCC patients suffer from recurrences and distant metastasis. With recent advances in genomics driven oncology and immunotherapeutics, the outcomes for afflicted HNSCC patients are likely to dramatically improve. However, there is an essential need for a better understanding of HNSCC neoantigen biology as these tumor specific antigens are the final common targets for immunotherapy. To address this key issue in immunotherapeutics, the work we propose will directly address the NIDCR RFA on “Neoantigen-Based Therapeutic Targeting of Head and Neck Cancers” by completing coupled mechanistic and translational studies. Supporting data provide a strong foundation in which to pursue the proposed work and include intriguing findings regarding neoantigen biology in our high- fidelity mouse models of HNSCC, novel clinical trial specimens in previously untreated patients and immunophenotyping approaches in difficult to treat recurrent and/or metastatic HNSCCs (RM HNSCC). The mouse oral carcinoma (MOC) model that we developed displays strong conservation to human HNSCC in its carcinogen origin, in vivo biology and response to anti-PD1 checkpoint blockade and represents a platform for mechanistic translational studies. Focusing on the MOC22 model, we identified this tumor line to possess both an endogenous retroviral expressed antigen (p15E) and a mutated ICAM1 (mICAM1) gene that yields a neoantigen. Antigen specific T cells for both of these antigens are present in growing MOC22 tumors. Importantly, specific vaccination experiments result in response for both antigens but surprisingly only the mICAM1 neoantigen provided protection from MOC22 tumor growth. These data have important implications for neoantigen biology highlighting the need to not only identity neoantigens but also to define induced responses in T cells. Coupled with these mechanistic approaches, we have initiated a novel neoadjuvant pembrolizumab clinical trial that has shown surprising clinical results and highlights this approach as an ideal setting in which to address neoantigen biology. Finally, we have immunophenotyped RM HNSCC tumor samples towards understanding the low 15-20% response rates to anti-PD1 therapy. These supporting data will be used to interrogate neoantigen mechanistic studies in the MOC model, define neoantigen landscapes in neoadjuvant pembrolizumab treated samples using novel screening methodologies and define single cell RNA- Sequencing transcriptome in antigen specific T cells. Finally, we will further expand on reports of increased mutational burdens in the RM HNSCC setting to define whether this translates into neoantigen reactivity and the associated T cell transcriptome. In conclusion, these Aims together will directly address the goals of this NIDCR RFA that will ultimately provide therapeutic benefit for HNSCC patients.

项目摘要在此应用程序中，我们组建了一个多学科团队，以执行综合机理和转化程序以定义头颈部鳞状细胞癌（HNSCC）中的新抗原生物学。尽管多模式治疗的进展，但大量的HNSCC患者患有复发和遥远的转移。随着基因组学的最新进展，肿瘤学和免疫治疗药，受苦HNSCC患者的结果可能会大大改善。但是，有必要为了更好地了解HNSCC新抗原生物学，因为这些肿瘤特异性抗原是最终的免疫疗法的常见靶标。为了解决免疫疗法的关键问题，我们提出的工作将直接解决“基于新抗原的头颈癌的治疗靶向”上的NIDCR RFA。通过完成耦合的机械和翻译研究。支持数据为在我们的高中，要从事拟议的工作，并包括有关新抗原生物学的有趣发现 HNSCC的保真小鼠模型，以前未经治疗的患者的新型临床试验标本和难以治疗复发和/或转移性HNSCC（RM HNSCC）的免疫表型方法。我们开发的小鼠口服癌（MOC）模型显示出对人类HNSCC的强烈保护致癌作者，体内生物学和对抗PD1检查点封锁的反应，代表了一个平台机械翻译研究。关注MOC22模型，我们确定了这条肿瘤线内源性逆转录病毒表达抗原（p15e）和突变的ICAM1（MIGAM1）基因，该基因产生A 新抗原。这两种抗原的抗原特异性T细胞都存在于生长的MOC22肿瘤中。重要的是，特定的疫苗接种实验导致两种抗原的反应，但令人惊讶的是 MIGAM1 Neoantigen提供了MOC22肿瘤生长的保护。这些数据具有重要的含义对于新抗原生物学，强调不仅需要身份新抗原，而且需要定义的诱导 T细胞中的反应。再加上这些机械方法，我们发起了一种新型的新辅助 Pembrolizumab临床试验表现出令人惊讶的临床结果，并将这种方法视为理想解决新抗原生物学的设置。最后，我们有免疫表型的RM HNSCC肿瘤旨在了解抗PD1治疗的15-20％缓解率的样本。这些支持数据将用于在MOC模型中询问新抗原机械研究，定义新抗原景观新辅助Pembrolizumab使用新型筛选方法处理的样品并定义单细胞RNA- 在抗原特异性T细胞中测序转录组。最后，我们将进一步扩展有关增加的报告 RM HNSCC设置中的突变伯良，以定义这是否转化为新抗原反应性和相关的T细胞转录组。总之，这些目标将共同直接解决这个目标 NIDCR RFA最终将为HNSCC患者提供治疗益处。