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）：有选择性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）的风险较高。免疫疗法对口腔鳞状细胞癌有希望，但由于它们诱导的免疫抑制而令人沮丧。另一种方法是对高危癌前病变患者进行免疫治疗。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的共享肿瘤抗原的保护性免疫。这一假说的基本原理是基于我们的研究表明，不典型增生癌前病变共享肿瘤抗原与口腔鳞状细胞癌的过度表达。最突出的共有抗原是表皮生长因子受体（EGFR）、晚期糖基化终产物（AGEs）的受体和MUC 1粘蛋白。测试我们假设的具体目标是：1。使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，并确定反应性是否靶向EGFR、EGFR和/或MUC 1。a.采用癌前病变致敏的树突状细胞体外刺激自体T细胞对癌前病变和口腔鳞癌的反应性。B.确定癌前病变致敏树突状细胞产生的免疫反应性靶向EGFR、EGFR和MUC 1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化为对癌前口腔病变和OSCC的保护性免疫反应。a.为了确定是否接种使用树突状细胞脉冲与裂解物的4 NQO诱导癌前病变细胞的局部免疫表型倾斜到反应性对癌前病变和口腔鳞癌。B.为了确定在体内接种与树突状细胞脉冲裂解物的4 NQO诱导癌前病变细胞刺激保护性免疫对癌前口腔病变和口腔鳞癌。C.确定在接种癌前病变致敏树突状细胞后产生的保护性免疫反应性靶向EGFR、EGFR和MUC 1的程度。D.为了确定是否接种树突状细胞脉冲与肽来源于EGFR，EGFR和MUC 1将赋予保护性免疫反应性癌前病变及其进展为口腔鳞状细胞癌。这些研究有望表明，针对癌前病变的疫苗接种可刺激针对癌前病变和OSCC的免疫力。鉴定针对其引发保护性免疫的靶抗原允许将来自这些抗原的肽用于病变和OSCC高风险患者的疫苗中。 公共卫生相关性：口腔鳞状细胞癌是世界上第6大常见肿瘤，5年生存率低于50%。拟议的研究与减少口腔癌从癌前病变发展为口腔癌的目标直接相关。