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。

• 批准号: 7928678
• 负责人: M. Rita Young
• 金额: $ 10万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/7928678
• 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; Immunotherapy; In Vitro; Incidence; Laboratories; Lead; Lesion; Leukoplakia; Lip structure; Malignant Neoplasms; Medicine; Modeling; Mucin-1 Staining Method; Mucins; Mus; Nitroquinolines; Operative Surgical Procedures; Oral; Otolaryngology; Oxides; Patients; Peptides; Phenotype; Physiologic pulse; Population; Premalignant; Recurrence; 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; public health relevance; receptor; response

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Oral squamous cell carcinoma is the 6th most common neoplasm in the world with a 5 year survival of less than 50%. The proposed studies have direct relevance to the goal of reducing oral cancer development from premalignant oral lesions.

描述（由申请人提供）：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癌（OSCC）的风险很高。免疫疗法对口腔鳞癌有希望，但因其引起的免疫抑制而令人沮丧。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，以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与 OSCC 共同存在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. 使用用自体癌前病变细胞脉冲的树突状细胞，在体外刺激患者 T 细胞对癌前病变和 OSCC 的反应性，并确定反应性是否针对 EGFR、RAGE 和/或 MUC1。一个。体外使用癌前病变脉冲树突状细胞来刺激自体 T 细胞对癌前病变和 OSCC 的反应性。 b.确定针对 EGFR、RAGE 和 MUC1 的癌前病变脉冲树突状细胞产生的免疫反应性的程度。 2. 在致癌物诱导的癌前病变小鼠模型中，将癌前口腔病变内的免疫表型转变为针对癌前口腔病变和 OSCC 的保护性免疫反应。一个。确定使用 4NQO 诱导的癌前病变细胞裂解物脉冲的树突状细胞进行疫苗接种是否会使局部免疫表型偏向针对癌前病变和 OSCC 的反应性。 b.体内确定用 4NQO 诱导的癌前病变细胞裂解物脉冲的树突状细胞疫苗接种是否会刺激针对口腔癌前病变和 OSCC 的保护性免疫。 c.确定针对 EGFR、RAGE 和 MUC1 的癌前病变脉冲树突状细胞接种疫苗后产生的保护性免疫反应的程度。 d.确定用源自 EGFR、RAGE 和 MUC1 的肽脉冲的树突状细胞进行疫苗接种是否会对癌前病变及其进展为 OSCC 产生保护性免疫反应。这些研究预计将表明针对癌前口腔病变的疫苗接种可刺激针对癌前病变和口腔鳞癌的免疫力。识别引起保护性免疫的靶抗原允许将这些抗原的肽用于疫苗中，用于针对病变和 OSCC 高风险的患者。 公共卫生相关性：口腔鳞状细胞癌是世界上第六大常见肿瘤，5 年生存率低于 50%。拟议的研究与减少口腔癌前病变发展为口腔癌的目标直接相关。