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

Novel strategy combined with targeted radiation therapy unleashes potentantitumor immunity in HPV + head and neck cancer

与靶向放射治疗相结合的新策略可释放 HPV 头颈癌的潜在抗肿瘤免疫力

基本信息

批准号：
10418815
负责人：
Chien-Fu Hung
金额：
$ 18.76万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418815
关键词：
Albumins Antigen Presentation Antigens Biological Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CXCL10 gene CXCL9 gene Cancer Model Chimeric Proteins Clonality Colon Adenocarcinoma Cross Presentation Cytotoxic T-Lymphocytes Data Dendritic Cells Development Exhibits FLT3 gene FLT3 ligand Face Fc Receptor Future Gene Expression Generations Genetic Half-Life Head and Neck Cancer Human Human Papillomavirus Immunity Immunotherapeutic agent Inflammatory Injections Interferon Type II Interferon-alpha Intuition Kinetics Knockout Mice Leucine Zippers Ligands MC38 Malignant Neoplasms Mediating Medical Memory Modeling Morbidity - disease rate Mus Names Papillomavirus Transforming Protein E6 Patients Play Population Process Production Public Health Radiation therapy Recycling Role Serum Proteins Stains T cell receptor repertoire sequencing T cell response T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes T-cell diversity TNF gene Therapeutic Time Transcription Factor 3 Treatment Efficacy Tumor Antigens Tumor Burden Tumor Immunity Tumor-Derived activating transcription factor adaptive immunity anti-tumor immune response bZIP Domain cancer type chemokine chemoradiation cytokine cytotoxic CD8 T cells effective therapy immunogenicity improved in vivo in vivo imaging system inflammatory milieu innovation lymph nodes lymphoid neoplasm mouse model neoantigens neonatal Fc receptor neoplastic cell novel novel strategies oral HPV-positive head and neck cancers pre-clinical progenitor secondary lymphoid organ standard of care therapeutically effective trafficking tumor tumor microenvironment tumor progression tumor specificity uptake virus related cancer

项目摘要

Project Summary/Abstract The overwhelming public health burden of HPV-associated head and neck cancer (HNC) has created great demand for novel, broadly effective therapies with reduced treatment morbidity and improved long term survival. While targeting HPV antigens in HPV+ cancers may be intuitive, these strategies have not demonstrated clear treatment efficacy, potentially due to the importance of neoantigen-specific cytotoxic T cell immunity in the long- term control of all cancers, including viral-associated cancer (1). Devising an off-the-shelf, broadly effective therapeutic strategy that can easily be combined with standard-of-care chemoradiation and is capable of potentiating both HPV- and neoantigen-specific CD8+ T cell immunity in HPV-associated HNC could prove widely efficacious. The generation of tumor-specific CD8+ T cell immunity requires potent antigen presentation by dendritic cells (DCs) since tumor cells do not efficiently present relevant CD8+ T cell epitopes. Murine CD103+ and CD8a+ DCs (cDC1s) are known for their ability to process exogenous antigen and potently cross-present to CD8+ T cells. Because of this, innovative strategies to enhance cross-presenting DC subsets could robustly induce HPV- and neoantigen-specific immunity and have great therapeutic potential in the treatment of HPV- associated HNC. FMS-like tyrosine kinase 3 ligand (Flt3L) is a cytokine that expands and differentiates DC precursors to murine cDC1s, but therapeutic potential of Flt3L is limited because of its short half-life and global distribution in vivo. We have overcome the described issues of Flt3L by generating a genetic fusion of Albumin (Alb) to Flt3L, named Albumin-Flt3L (Alb-Flt3L). Alb has a long half-life due to neonatal Fc receptor (FcRn)- mediated transcytolic recycling, and exhibits trafficking to the LNs as a serum protein. The novel immunotherapeutic Alb-Flt3L fusion protein exhibits increased half-life and selective accumulation in LN and tumor compared to native Flt3L. Alb-Flt3L is able to expand cross-presenting DC populations in vivo following a single injection. Alb-Flt3L + targeted radiation therapy (RT) to release tumor antigens and enhance tumor immunogenicity is able to control tumor progression and extend survival of colon adenocarcinoma MC38 tumor bearing mice. Impressively, Alb-Flt3L + RT induced spontaneous tumor neoantigen-specific T cell responses, in addition to efficacy as a single agent in PANC02 model. In this proposal, the ability of Alb-Flt3L to promote HPV- and neoantigen-specific cytotoxic T cell antitumor immunity through the expansion of cross-presenting DCs and subsequent tumor control in multiple HPV-associated HNC models will be investigated. HPV- and neoantigen- specific CD8+ T cell responses will be evaluated using tetramer and TCR sequencing approaches. The mechanism by which Alb-Flt3L mediates its immunostimulatory function will also be interrogated using appropriate deficient mouse models. Successful completion of this proposal will generate valuable preclinical and mechanistic data regarding the therapeutic potential of Alb-Flt3L, a novel immunotherapeutic with potential efficacy as a universal strategy to treat HPV-associated HNC as well as many other types of cancer.

项目总结/文摘