权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting the innate immune response in HNSCC

针对 HNSCC 的先天免疫反应

基本信息

批准号：
9980195
负责人：
Judith A VARNER
金额：
$ 46.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980195
关键词：
Animal Model Automobile Driving Biological Blood Circulation CD8-Positive T-Lymphocytes Cancer Etiology Cessation of life Chemotherapy and/or radiation Clinical Complex Country Disease FRAP1 gene Gene Expression Profile Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Human Papillomavirus Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Markers Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Infection Inflammatory Innate Immune Response Interferon Type II Interleukin-10 Interleukin-12 Malignant Neoplasms Mediating Metastatic/Recurrent Molecular Myeloid Cells Myeloid-derived suppressor cells Nature Nivolumab Patient-Focused Outcomes Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphotransferases Proteins Role Sampling Signal Pathway Signal Transduction System T cell response T cell therapy T memory cell T-Lymphocyte Testing Therapeutic Tissues Transforming Growth Factor beta Tumor-associated macrophages United States Woman animal tissue anti-PD-1 anti-tumor immune response arginase cancer therapy combat cytotoxic cytotoxic CD8 T cells immunogenic improved improved outcome macrophage malignant mouth neoplasm malignant oropharynx neoplasm men mortality new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics phase III trial polarized cell predictive signature recruit response standard of care targeted agent therapeutic target treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

Abstract The immune system is a complex but highly plastic biological defense system that normally protects the host against infection and damage. However, in some disease states, such as cancer, the usually well-orchestrated immune response fails to protect the host and instead exacerbates disease. Because the immune system is highly plastic, however, novel therapeutics may be able to restore normal immune responses that combat cancer. There is a critical need to develop novel therapies for oral cancers, such as head and neck squamous cell carcinoma (HNSCC), a deadly and disfiguring disease that accounts for an estimated 59,340 cases (43,390 men and 15,950 women) and 12,290 deaths each year in the United States. The incidence of HNSCC is rapidly rising in the United States and worldwide, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. While current immune therapies hold new promise for the treatment of cancer, the checkpoint inhibitor nivolumab (anti-PD-1) recently demonstrated only modest single agent activity in recurrent/metastatic HNSCC, as one-year survival and response rates were only 36% and 13%, respectively, in a Phase 3 trial. Improved therapeutic approaches that target additional mechanisms of immune escape in combination with checkpoint inhibitors could hold promise for this disease. Our recent studies (Nature 2016) showed that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune escape. We found that two macrophage proteins, phosphatidylinositol-4,5-bisphosphate 3-kinase gamma PI3Kγ inhibition repolarized macrophages and synergized with anti-PD-1 to enhance recruitment and activation of IFNγ+ cytotoxic CD8+ T cells. These results indicate that therapeutic strategies that target TAMs as well as T cell checkpoints could improve HNSCC patient outcomes. We propose to test the overall hypothesis that therapeutic strategies that block macrophage-mediated immune suppression will synergize with T cell targeted therapeutics to improve outcomes in HNSCC disease. The specific aims of this proposal are: 1) To determine how immune suppressive myeloid cells are recruited to HNSCC tumors. 2) To identify how myeloid cell polarization is controlled during HNSCC tumor progression. 3) To identify novel immune therapeutic strategies and immune biomarkers for HNSCC disease.

摘要