Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.

免疫疗法可预防口腔永久病变复发和口腔癌。

基本信息

批准号：
8197942
负责人：
M. Rita Young
金额：
$ 25.36万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197942
关键词：
4-Nitroquinoline-1-oxide Advanced Glycosylation End Products Antigen Targeting Antigens Autologous Carcinogens Cells Characteristics Collection Common Neoplasm Dendritic Cell Vaccine Dendritic Cells Dental Development Epidermal Growth Factor Receptor Goals Head and Neck Surgery Human Immune Immunity Immunosuppression Immunotherapy In Vitro Incidence Laboratories Lead Lesion Leukoplakia Lip structure Malignant Neoplasms Medicine Modeling Mucin-1 Staining Method Mucins Mus Operative Surgical Procedures Oral Otolaryngology Patients Peptides Phenotype Physiologic pulse Population Premalignant Recurrence Regulatory T-Lymphocyte Secondary Lesion Sublingual Region T-Lymphocyte Testing Thick Tongue Tumor Antigens Vaccination Vaccines base cDNA Arrays college high risk in vitro testing in vivo malignant mouth neoplasm monocyte mouse model mouth squamous cell carcinoma oral lesion overexpression peripheral blood prevent receptor response

项目摘要

Patients with select premalignant oral lesions have a high risk of secondary lesions and oral squamous cell carcinoma (OSCC). Immune therapies hold promise for OSCC, but are discouraged by the immune suppression they induce. An alternative is immune treatment of patients with high risk premalignant lesions. We hypothesize that oral premalignant lesions can be used in dendritic cell vaccines to stimulate protective immunity targeting shared tumor antigens on premalignant lesions and OSCC. The rationale for this hypothesis is based on our studies showing that dysplastic premalignant lesions share overexpression of tumor antigens with OSCC. The most prominent shared antigens are epidermal growth factor receptor (EGFR), the receptor for advanced glycation end products (RAGE) and the MUC1 mucin. The specific aims that will test our hypothesis are: 1. To stimulate patient T-cell reactivity in vitro to premalignant lesions and OSCC using dendritic cells pulsed with autologous premalignant lesion cells and to determine if reactivity targets EGFR, RAGE and/or MUC1. a. To use premalignant lesion-pulsed dendritic cells in vitro to stimulate autologous T-cell reactivity to premalignant lesions and OSCC. b. To determine the extent to which the immune reactivity that is generated in response to premalignant lesion-pulsed dendritic cells is targeted at EGFR, RAGE and MUC1. 2. To skew the immune phenotype within premalignant oral lesions into protective immune reactivity against premalignant oral lesions and OSCC in a carcinogen-induced premalignant lesion mouse model. a. To determine if vaccination using dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells skews the local immune phenotype into reactivity against premalignant lesions and OSCC. b. To determine in vivo if vaccination with dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells stimulates protective immunity against premalignant oral lesions and OSCC. c. To determine the extent to which the protective immune reactivity that is generated in response to vaccination with premalignant lesion-pulsed dendritic cells is targeted at EGFR, RAGE and MUC1. d. To determine if vaccination with dendritic cells pulsed with peptides derived from EGFR, RAGE and MUC1 will confer protective immune reactivity to premalignant lesions and their progression to OSCC. These studies are expected to show that vaccination against premalignant oral lesions stimulates immunity against premalignant lesions and OSCC. Identifying the target antigens against which protective immunity is elicited allow use of peptides from these antigens in vaccines for patients at high risk for lesions and OSCC.

患有特定口腔癌前病变的患者发生继发性病变和口腔鳞状细胞的风险很高癌（OSCC）。免疫疗法对口腔鳞癌有希望，但因免疫疗法的阻碍而受到阻碍它们引起的抑制。另一种选择是对具有高风险癌前病变的患者进行免疫治疗。我们假设口腔癌前病变可用于树突状细胞疫苗来刺激针对癌前病变和 OSCC 上共有肿瘤抗原的保护性免疫。这一假设的基本原理是基于我们的研究表明，发育不良的癌前病变共有 OSCC 中肿瘤抗原的过度表达。最突出的共享抗原是表皮生长因子受体 (EGFR)、晚期糖基化终末产物受体 (RAGE) 和 MUC1 粘蛋白。检验我们假设的具体目标是： 1. 使用脉冲树突状细胞在体外刺激患者 T 细胞对癌前病变和 OSCC 的反应性与自体癌前病变细胞进行检测，以确定反应性是否针对 EGFR、RAGE 和/或 MUC1。一个。在体外使用癌前病变脉冲树突状细胞来刺激自体 T 细胞反应性癌前病变和 OSCC。 b.确定针对癌前病变产生的免疫反应性的程度损伤脉冲树突状细胞针对 EGFR、RAGE 和 MUC1。 2. 将癌前口腔病变内的免疫表型转变为针对以下物质的保护性免疫反应：致癌物诱导的癌前病变小鼠模型中的癌前口腔病变和 OSCC。一个。确定使用 4NQO 诱导的癌前细胞裂解物脉冲的树突状细胞进行疫苗接种是否有效病变细胞使局部免疫表型产生针对癌前病变和 OSCC 的反应性。 b.确定体内是否用 4NQO 诱导的裂解物脉冲的树突状细胞进行疫苗接种癌前病变细胞可刺激针对癌前口腔病变和口腔鳞癌的保护性免疫。 c.确定响应产生的保护性免疫反应的程度使用癌前病变脉冲树突状细胞进行疫苗接种的目标是 EGFR、RAGE 和 MUC1。 d.确定用 EGFR、RAGE 和衍生肽脉冲的树突状细胞疫苗接种是否有效 MUC1 将为癌前病变及其进展为 OSCC 提供保护性免疫反应性。这些研究预计将表明针对癌前口腔病变的疫苗接种可以刺激免疫力对抗癌前病变和 OSCC。识别保护性免疫所针对的靶抗原允许将这些抗原的肽用于疫苗中，用于患有病变和 OSCC 高风险的患者。