Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity

维生素 D 加塞来昔布疗法刺激瘤内免疫反应

• 批准号: 8390418
• 负责人: M. Rita Young
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8390418
• 关键词: Aging; Alcohol consumption; Antigens; Attention; Breast; CD34 gene; Cancer Vaccines; Cell Maturation; Cell physiology; Cells; Clinical; Clinical Trials; Clinical effectiveness; Combined Modality Therapy; Common Neoplasm; Cyclooxygenase Inhibitors; Defect; Dendritic Cells; Development; Diagnosis; Dihydroxycholecalciferols; Dinoprostone; Effectiveness; Endothelial Cells; Environment; Excision; Exposure to; Gulf War; Health; Immune; Immunologic Tests; Immunosuppression; Immunotherapeutic agent; In Vitro; Incidence; Interleukin-6; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Military Personnel; Modeling; Mus; Myeloid Cells; Newly Diagnosed; Operative Surgical Procedures; Outcome Measure; PTGS2 gene; Patients; Population; Production; Prostate; Radiosurgery; Recurrence; Regulatory T-Lymphocyte; Reporting; Risk Factors; Smoking; Stem cells; Suppressor-Effector T-Lymphocytes; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Vaccines; Veterans; Vitamin D; alternative treatment; base; cancer diagnosis; cancer recurrence; celecoxib; cell type; chemotherapy; comparison group; immune function; improved; inhibitor/antagonist; interest; macrophage; malignant mouth neoplasm; mouth squamous cell carcinoma; prevent; primary outcome; propellant; response; secondary outcome; tumor

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.

口腔鳞状细胞癌 (OSCC) 是一种侵袭性恶性肿瘤，其生存期为 5 年 过去 30 年，免疫治疗方法对于 OSCC 患者来说可能是替代方案。 不幸的是，OSCC患者存在由肿瘤诱导的免疫介导的严重免疫缺陷。 抑制细胞，包括肿瘤动员的 CD34+ 祖细胞和 Treg。 正在进行的 VA 绩效审查试验表明 1¿ ,25-二羟基维生素 D3 [1,25(OH)2D3] 诱导分化 然而，我们最近将免疫抑制性 CD34+ 祖细胞转化为免疫刺激性树突状细胞。 还表明，OSCC 通过刺激内皮细胞产生免疫抑制来诱导内皮细胞产生免疫抑制。 免疫抑制介质 PGE2，反过来又诱导其产生抑制介质 IL-6。PGE2 和 IL-6 都会刺激其他抑制性细胞类型，例如 M2 巨噬细胞和 Treg 细胞。 这项研究的假设是，OSCC 肿瘤中有益的 T 细胞反应性可以通过以下因素协同刺激： 阻断抑制性内皮细胞及其对其他抑制性细胞群的诱导，同时成熟 免疫抑制性 CD34+ 细胞转化为抗原呈递树突状细胞。 为了检验这一假设，新诊断的 OSCC 患者将接受 COX-2 抑制剂塞来昔布 和/或 1,25(OH)2D3，持续 3 周的癌症诊断和手术治疗之间的持续时间。 目标将测试联合治疗的免疫学和临床有效性： #1 阻断内皮细胞的抑制活性并增加刺激性树突的水平 T 细胞的反应性，协同增加肿瘤内 T 细胞的反应性，从而这些功能。 免疫分析将使用从未经治疗的患者或接受过治疗的患者身上取出的 OSCC 组织。 塞来考昔和/或 1,25(OH)2D3。 #2：通过协同刺激瘤内 T 细胞反应性来减少 OSCC 复发的发生 与塞来昔布一起阻断抑制内皮细胞活性，并与 1,25(OH)2D3 一起阻断成熟的 CD34+ 抑制细胞 细胞转变为 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 OSCC 的 T 细胞激活疫苗一起增强树突状细胞的成熟。 研究将适用于诱导免疫抑制细胞的其他类型的恶性肿瘤，包括肺癌 和前列腺癌，这在老龄化退伍军人群体中越来越突出。