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Characterization of Human Oral Cancer Initiating Cell (CIC) Antigens

人类口腔癌起始细胞 (CIC) 抗原的表征

基本信息

批准号：
8928281
负责人：
Qiao Li
金额：
$ 28.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928281
关键词：
Animal Model Antigen-Presenting Cells Antigens Autologous Dendritic Cells B-Lymphocytes Biology Cancer Patient Cancer Relapse Carcinoma Cells Clinical Clinical Trials Dendritic Cell Vaccine Dendritic Cells Development Disease Head and Neck Cancer Histologic Human Human Identifications Human Papillomavirus Immune Immunity Immunocompetent Immunotherapy In Vitro Malignant Epithelial Cell Malignant Neoplasms Malignant Squamous Cell Neoplasm Methods Mouth Neoplasms Mus Oral Oral cavity Oropharyngeal Oropharyngeal Neoplasms Oropharyngeal Squamous Cell Carcinoma Patients Population Research Proposals Resistance Specimen Staging Structure Therapeutic Tobacco Translating Treatment Efficacy Xenograft Model aldehyde dehydrogenases base cancer cell cancer therapy clinical application clinically relevant conventional therapy immunogenicity improved in vivo malignant breast neoplasm malignant mouth neoplasm melanoma member mouth squamous cell carcinoma novel outcome forecast response tumor

项目摘要

Oral cavity and oropharyngeal squamous cell carcinomas represent the majority of oral squamous cell cancers (OSCC). Oral cavity tumors and oropharynx have different biology; however, the clinical responses of both carcinomas are very low to current treatments available. Oral cavity cancer is mostly HPV negative, and is primarily a tobacco associated malignancy. Patients with oropharyngeal tumors tend to respond better to treatment and have a better prognosis when compared to stage-matched oral cavity cancer. Novel treatment is urgently needed to improve the therapeutic efficacy of this disease to prolong the survival of the patients with oral cavity cancer. We recently identified and characterized cancer initiating cell (CIC)-enriched populations in two histologically distinct murine tumors (squamous cell cancer SCC7 and melanoma D5) using aldehyde dehydrogenase (ALDH) as a marker, and evaluated their immunogenicity by administering CIC-based dendritic cell (DC) vaccines in two genetically different syngeneic immunocompetent hosts. In addition, our team members have used ALDH as a specific marker and identified human head and neck cancer and breast cancer initiating cells respectively. Most of the current immune therapeutic methods involve individualized approaches, which significantly limits the clinical application of these methods. To help with the development of “off-the-shelf” immunotherapies for cancer patients, cancer antigens need to be defined. We hypothesize that there exist OSCC CIC-associate/specific antigen(s) which are responsible for CIC antigenicity/immunogenicity to elicit host anti-CIC immunity. Specifically targeting cancer initiating cells will enhance the efficacy of cancer therapy. To this end, we propose to analyze the antigenicity/immunogenicity of ALDHhigh human oral cavity CICs vs. ALDHlow oral cavity non-CICs. Significantly higher antigenicity/immunogenicity of ALDHhigh human oral cavity CICs to confer anti-CIC immunity will strongly suggest the existence of unique oral cavity CIC antigens, and thus provide the rationale to isolate and characterize these antigens. Identification and characterization of immunologically and clinically relevant human oral CIC antigens as proposed to use human tumor specimens may demonstrate the proof of principle that previous findings in our animal models may be translated into human clinical trials in an autologous DC vaccine setting to present OSCC CIC specific antigen (s).

口腔和口咽鳞状细胞癌占口腔鳞状细胞癌的大多数（口腔鳞状细胞癌）。口腔肿瘤和口咽部肿瘤具有不同的生物学特性，然而，癌症的发病率非常低。口腔癌大多是HPV阴性，主要是烟草相关的恶性肿瘤。口咽部肿瘤的患者往往对与分期匹配的口腔癌相比，治疗和预后更好。新疗法是迫切需要提高该病的治疗效果，以延长患者的生存期，口腔癌。最近，我们鉴定并表征了在大肠杆菌中富含癌症起始细胞（CIC）的群体。两种组织学上不同的鼠肿瘤（鳞状细胞癌SCC 7和黑色素瘤D5），作为标记物，并通过施用基于CIC的树突状细胞来评估它们的免疫原性。细胞（DC）疫苗在两种遗传上不同的同基因免疫活性宿主中的免疫应答。此外，我们的团队成员们使用ALDH作为一种特异性标志物，分别是癌症起始细胞。目前大多数免疫治疗方法涉及个体化这极大地限制了这些方法的临床应用。帮助发展对于癌症患者的“现成”免疫疗法，需要定义癌症抗原。我们假设存在OSCC CIC相关/特异性抗原，其负责CIC抗原性/免疫原性引发宿主的抗CIC免疫特异性靶向癌症起始细胞将增强癌症的疗效疗法为此，我们建议分析ALDH高人口腔的抗原性/免疫原性， CIC与ALDH低口腔非CIC。ALDH高人的抗原性/免疫原性显着更高口腔CIC赋予抗CIC免疫力将强烈提示存在独特的口腔CIC 抗原，从而提供了分离和表征这些抗原的基本原理。识别和免疫学和临床相关的人口服CIC抗原的表征，肿瘤标本可以证明我们以前在动物模型中的发现可能是在自体DC疫苗环境中转化为人类临床试验，以呈递OSCC CIC特异性抗原（s）。