Immunotherapy to prevent oral permalignant lesion recurrence and oral cancer.

有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)。免疫疗法对口腔鳞状细胞癌有希望，但受到免疫的阻碍 它们引起的压抑。另一种选择是对有高危癌前病变的患者进行免疫治疗。 我们假设口腔癌前病变可以用于树突状细胞疫苗以刺激 针对癌前病变和口腔鳞癌的共同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 口腔鳞癌中肿瘤抗原的过度表达。最突出的共同抗原是表皮生长 因子受体(EGFR)、晚期糖基化终末产物受体(RAGE)和粘蛋白1。 检验我们假设的具体目标是： 1.用冲击树突状细胞体外刺激患者T细胞对癌前病变和口腔鳞癌的反应性 与自体癌前病变细胞进行比较，并确定反应性靶点是否为EGFR、RAGE和/或MUC1。 A.使用癌前病变致敏的树突状细胞体外刺激自体T细胞反应性 癌前病变和口腔鳞癌。 B.确定对癌前病变所产生的免疫反应性的程度 病变冲击的树突状细胞以EGFR、RAGE和MUC1为靶点。 2.将口腔癌前病变的免疫表型转变为保护性免疫反应 致癌物诱导的口腔癌前病变小鼠模型中的口腔癌前病变和口腔鳞癌。 A.确定是否使用4NQO诱导的癌前病变裂解物冲击的树突状细胞接种 病变细胞将局部免疫表型转化为对癌前病变和口腔鳞癌的反应。 B.在体内确定用4NQO诱导的裂解产物冲击的树突状细胞接种 癌前病变细胞刺激对癌前口腔病变和口腔鳞癌的保护性免疫。 C.确定在多大程度上产生的保护性免疫反应性 癌前病变致敏的树突状细胞疫苗针对的是EGFR、RAGE和MUC1。 D.确定用由EGFR、RAGE和AGE来源的多肽冲击的树突状细胞接种 MUC1将赋予癌前病变及其进展为口腔鳞癌的保护性免疫反应性。 这些研究有望表明，针对口腔癌前病变的疫苗接种可以刺激免疫力。 对抗癌前病变和口腔鳞癌。识别保护性免疫所针对的目标抗原 该疫苗允许将这些抗原的多肽用于病变和口腔鳞癌高危患者的疫苗。

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.