Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.

描述（由申请人提供）：患有特定口腔癌前病变的患者继发性病变和口腔鳞状细胞癌（OSCC）的风险很高。免疫疗法对OSCC有希望，但由于它们诱导的免疫抑制而不受欢迎。另一种选择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具有肿瘤抗原的过表达。最突出的共同抗原是表皮生长因子受体（EGFR）、晚期糖基化终产物受体（RAGE）和MUC1粘蛋白。检验我们假设的具体目标是：1。使用树突状细胞与自体癌前病变细胞脉冲刺激患者t细胞体外对癌前病变和OSCC的反应性，并确定反应性是否针对EGFR、RAGE和/或MUC1。a.体外使用癌前病变脉冲树突状细胞刺激自体t细胞对癌前病变和OSCC的反应性。b.确定肿瘤前病变脉冲树突状细胞产生的免疫反应性在多大程度上针对EGFR、RAGE和MUC1。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扭曲为针对癌前口腔病变和OSCC的保护性免疫反应性。a.确定用4nqo诱导的癌前病变细胞裂解物脉冲的树突状细胞接种疫苗是否使局部免疫表型扭曲为对癌前病变和OSCC的反应性。b.在体内确定用4nqo诱导的癌前病变细胞裂解物脉冲树突状细胞接种疫苗是否能刺激对癌前口腔病变和OSCC的保护性免疫。c.确定接种癌前病变脉冲树突状细胞后产生的保护性免疫反应性在多大程度上针对EGFR、RAGE和MUC1。d.确定用来源于EGFR、RAGE和MUC1的肽脉冲树突状细胞接种疫苗是否会赋予对癌前病变及其向OSCC进展的保护性免疫反应性。这些研究预计将表明，针对癌前口腔病变的疫苗接种可刺激对癌前病变和OSCC的免疫。识别可引起保护性免疫的靶抗原，可将这些抗原的肽用于针对病变和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六大最常见的肿瘤，5年生存率低于50%。所提出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。

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.