Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity

口腔鳞状细胞癌(OSCC)是一种侵袭性的恶性肿瘤，其存活期为5年。 在过去的30年里一直是50%。口腔鳞癌患者的免疫治疗方法可能是替代方案 治疗。不幸的是，口腔鳞癌患者存在由肿瘤诱导免疫介导的严重免疫缺陷 抑制性细胞包括肿瘤动员的CD34+祖细胞和Treg。我们过去的体外研究和我们的 正在进行的VA优秀奖审查试验表明，1，25-二羟基维生素D3[1，25(OH)2D3]诱导分化 免疫抑制CD34+祖细胞转化为免疫刺激树突状细胞。然而，我们最近 还表明口腔鳞状细胞癌通过刺激内皮细胞产生 免疫抑制介质PGE2，进而诱导它们产生抑制介质 IL-6。PGE2和IL-6都能刺激其他类型的抑制性细胞，如M2巨噬细胞和Treg细胞。 这项研究的假设是口腔鳞癌肿瘤中有益的T细胞反应性可以被协同刺激 阻断抑制性内皮细胞及其对其他抑制性细胞群的诱导作用 免疫抑制CD34+细胞转化为抗原提呈树突状细胞。 为了验证这一假设，新诊断的口腔鳞癌患者将接受环氧合酶-2抑制剂塞来昔布的治疗。 和/或1，25(OH)2D3，从癌症诊断到手术治疗之间的3周时间。以下是 AIMS将测试联合治疗的免疫学和临床疗效： #1阻断内皮细胞的抑制活性并增加具有刺激作用的树突状细胞的水平 对T细胞的反应性，从而协同增强肿瘤内的T细胞反应性。这些功能 免疫分析将使用从未经治疗的患者或接受治疗的患者身上取出的口腔鳞癌组织 塞来昔布和/或1，25(OH)2D3。 #2：通过协同刺激肿瘤内T细胞活性来减少口腔鳞癌复发的发生 塞来昔布阻断抑制内皮细胞活性，1，25(OH)2D3阻断成熟CD34+抑制因子 转化为T细胞刺激性树突状细胞。 这些研究的长期应用是使用阻断免疫抑制细胞和 与针对口腔鳞癌的T细胞激活疫苗一起促进树突状细胞的成熟。这些研究的结果 研究将适用于其他类型的恶性肿瘤，包括肺在内的诱导免疫抑制细胞的肿瘤 以及前列腺癌，这在老龄化的退伍军人人口中正变得越来越突出。

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with a 5 year survival that has remained at 50% for the last 30 years. Immunotherapeutic approaches for OSCC patients may be alternative treatments. Unfortunately, OSCC patients have profound immune defects mediated by tumor-induced immune suppressor cells including tumor-mobilized CD34+ progenitor cells and Treg. Our past in vitro studies and our ongoing VA merit-review trial are showing that 1¿,25-dihydroxyvitamin D3 [1,25(OH)2D3] induces differentiation of immune suppressive CD34+ progenitor cells into immune stimulatory dendritic cells. However, we recently also showed that OSCC induce endothelial cells to become immune inhibitory by stimulating them to produce the immune suppressive mediator PGE2 which, in turn, induces their production of the suppressive mediator IL-6. Both PGE2 and IL-6 stimulate other suppressive cell types such as M2 macrophages and Treg cells. The hypothesis of this study is beneficial T-cell reactivity in OSCC tumors can be synergistically stimulated by blocking suppressor endothelial cells and their induction of other inhibitory cell populations while also maturing immune inhibitory CD34+ cells into antigen-presenting dendritic cells. To test this hypothesis, newly diagnosed OSCC patients will be administered the COX-2 inhibitor celecoxib and/or 1,25(OH)2D3 for the 3 week duration between cancer diagnosis and surgical treatment. The following aims will test the immunological and clinical effectiveness of the combination treatment: #1 To block the suppressive activity of endothelial cells and increase the levels of dendritic that are stimulatory to T-cell reactivity, thereby synergistically increasing intratumoral T-cell reactivity. These functional immune analyses will use OSCC tissues removed from untreated patients or patients treated with celecoxib and/or 1,25(OH)2D3. #2: To reduce development of OSCC recurrences by synergistically stimulating intratumoral T-cell reactivity with celecoxib to block suppressor endothelial cell activity and 1,25(OH)2D3 to mature CD34+ suppressor cells into T-cell stimulatory dendritic cells. The long-term application of these studies is to use treatments that block immune suppressor cells and enhance dendritic cell maturation together with T-cell activation vaccines targeting OSCC. The results of these studies will be applicable to other types of malignancies that induce immune suppressive cells, including lung and prostate cancer, which are increasing in prominence in the aging Veterans population.