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.

项目概要/摘要 HPV 相关头颈癌 (HNC) 给公众带来了巨大的健康负担对新的、广泛有效的疗法的需求，以降低治疗发病率并提高长期生存率。虽然针对 HPV+ 癌症中的 HPV 抗原可能很直观，但这些策略尚未得到明确证明治疗效果，可能是由于新抗原特异性细胞毒性 T 细胞免疫在长期治疗中的重要性所有癌症的长期控制，包括病毒相关癌症 (1)。设计一种现成的、广泛有效的可以轻松与标准护理放化疗结合的治疗策略，并且能够增强 HPV 相关 HNC 中 HPV 和新抗原特异性 CD8+ T 细胞免疫可能证明广泛有效。肿瘤特异性 CD8+ T 细胞免疫的产生需要有效的抗原呈递由于肿瘤细胞不能有效地呈现相关的 CD8+ T 细胞表位，因此由树突状细胞 (DC) 产生。鼠CD103+ 和 CD8a+ DC (cDC1) 以其处理外源抗原并有效交叉提呈到 CD8+ T 细胞。正因为如此，增强交叉呈现 DC 子集的创新策略可以稳健地诱导 HPV 和新抗原特异性免疫，在治疗 HPV 方面具有巨大的治疗潜力相关的 HNC。 FMS 样酪氨酸激酶 3 配体 (Flt3L) 是一种扩增和分化 DC 的细胞因子 Flt3L 是小鼠 cDC1 的前体，但由于其半衰期短且全局性，其治疗潜力有限体内分布。我们通过生成白蛋白的基因融合克服了 Flt3L 的上述问题 (Alb) 至 Flt3L，命名为白蛋白-Flt3L (Alb-Flt3L)。由于新生儿 Fc 受体 (FcRn)，Alb 的半衰期较长 - 介导跨细胞再循环，并作为血清蛋白运输至 LN。小说免疫治疗 Alb-Flt3L 融合蛋白在 LN 和 LN 中表现出半衰期延长和选择性积累与天然 Flt3L 相比，肿瘤。 Alb-Flt3L 能够在体内扩增交叉呈递的 DC 群体单次注射。 Alb-Flt3L + 靶向放射治疗（RT）释放肿瘤抗原并增强肿瘤免疫原性能够控制肿瘤进展并延长结肠腺癌 MC38 肿瘤的生存期承载老鼠。令人印象深刻的是，Alb-Flt3L + RT 诱导自发肿瘤新抗原特异性 T 细胞反应，除了在 PANC02 模型中作为单一药物的功效之外。在该提案中，Alb-Flt3L 促进 HPV- 通过交叉呈递 DC 的扩增和新抗原特异性细胞毒性 T 细胞抗肿瘤免疫随后将研究多种 HPV 相关 HNC 模型中的肿瘤控制。 HPV-和新抗原- 将使用四聚体和 TCR 测序方法评估特定的 CD8+ T 细胞反应。这 Alb-Flt3L 介导其免疫刺激功能的机制也将通过使用适当的缺陷小鼠模型。该提案的成功完成将产生有价值的临床前研究成果关于 Alb-Flt3L 治疗潜力的机制数据，一种具有潜力的新型免疫疗法作为治疗 HPV 相关 HNC 以及许多其他类型癌症的通用策略。