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代表大多数口腔鳞状细胞癌（OSCC）。口腔肿瘤和口咽具有不同的生物学；但是，两者的临床反应癌对当前治疗非常低。口腔癌主要为HPV阴性，是首先是烟草相关的恶性肿瘤。口咽肿瘤的患者倾向于反应更好与阶段匹配的口腔癌相比，治疗和预后更好。新型治疗是迫切需要提高这种疾病的治疗效率，以延长患者的生存口腔癌。我们最近确定并表征了癌症启动细胞（CIC）富含细胞的种群使用醛的两个组织学不同的鼠类肿瘤（鳞状细胞癌SCC7和黑色素瘤D5）脱氢酶（ALDH）作为标记物，并通过施用基于CIC的树突状态评估其免疫原性两种遗传上不同的合成性免疫能力宿主中的细胞（DC）疫苗。此外，我们的团队成员已使用ALDH作为特定标记，并确定了人头和颈部癌和乳房癌症启动细胞。当前的大多数免疫治疗方法涉及个性化的方法，这显着限制了这些方法的临床应用。帮助发展为癌症患者的“现成”免疫疗法，需要定义癌症抗原。我们假设这一点存在负责CIC抗原性/免疫原性的OSCC CIC缔合/特异性抗原引起宿主抗CIC免疫。特别靶向癌症启动细胞将提高癌症的效率治疗。为此，我们建议分析Aldhhigh人口腔的抗原性/免疫原性 CICS vs. Aldhlow口腔非摄入。 Aldhhigh人类的抗原性/免疫原性明显更高口腔CIC赋予抗CIC免疫会强烈表明存在独特的口腔CIC 抗原，因此提供了分离和表征这些抗原的基本原理。识别和提议使用人类的免疫学和临床相关的人口腔CIC抗原的表征肿瘤标本可能证明了原则的证据，即我们的动物模型中以前的发现可能是在自体直流疫苗设置中转化为人类临床试验，以呈现OSCC CIC特异性抗原（S）。