Modulation of Tumor CEA Levels for an Anti-CEA Vaccine

抗 CEA 疫苗的肿瘤 CEA 水平调节

• 批准号: 6932740
• 负责人: WILLIAM E. CARSON
• 金额: $ 29.53万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-18 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932740
• 关键词: MHC class I antigen; Poxviridae; biopsy; carcinoembryonal antigen; clinical research; clinical trial phase I; colony stimulating factor; combination therapy; enzyme linked immunosorbent assay; human subject; human therapy evaluation; immune response; immunocytochemistry; interferon alpha; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; recombinant virus; transfection /expression vector; vaccinia virus

DESCRIPTION (provided by applicant): Vaccination strategies represent an exciting new approach to the treatment of CEA-expressing malignancies. The present trial will employ two novel anti-CEA vaccines; Vaccinia-CEA(6D)-TRICOM and Fowlpox-CEA(6D)-TRICOM. These recombinant (r) poxvirus vectors infect professional antigen presenting cells which in turn present peptides derived from the full length CEA molecule. These viral vectors also direct the expression of three co-stimulatory molecules (B7-1, ICAM-1, and LFA-3) each of which is capable of providing a critical second activating signal to antigen-specific T cells. Priming with the vaccinia vector and boosting with the fowlpox vector enhances the formation of a CEA-specific T cell response. GM-CSF is also given at the vaccination site as it promotes the activation, maturation, and migration of antigen presenting cells. We plan to evaluate the safety and efficacy of the vaccine regimen when combined with interferon-alpha-2b (IFN-a2b). IFN-a will be combined with this vaccine regimen because of its ability to rapidly upregulate CEA expression in patient tumor cells. Also, IFN-a upregulates tumor cell expression of MHC class I molecules that are critical for the presentation of tumor antigens to cytolytic T cells. We therefore hypothesize that IFN-a treatments will increase CEA and MHC Class I expression on patient tumor cells leading to an improved anti-CEA immune response following vaccination. All patients will receive a priming vaccination with rVaccinia-CEA(6D)-TRICOM followed at monthly intervals by boosting vaccinations with rFowlpox-CEA(6D)-TRICOM. All vaccinations will be given with GM-CSF (sargramostim) 100 mcg subcutaneously (s.c.) at the vaccine site starting on the day of vaccination and continuing for a total of 4 days. Patients will receive three s.c. doses of IFN-a2b following each vaccination. The IFN-a2b component of therapy will be dose-escalated over four dose levels (1, 3, 6, or 9 million units) in cohorts of three patients. Tumors will be biopsied and examined to determine the effect of IFN-a2b administration on tumor expression of CEA and MHC class I. The formation of an anti-CEA T cell response will be evaluated by a panel of immunologic correlative studies. These analyses will allow us to determine whether the expression of the CEA tumor antigen can be modulated by cytokine treatment and if this translates into an improved anti-tumor response.

描述（由申请人提供）：疫苗接种策略代表了一种令人兴奋的治疗表达 CEA 的恶性肿瘤的新方法。目前的试验将采用两种新型抗 CEA 疫苗；牛痘-CEA(6D)-TRICOM 和鸡痘-CEA(6D)-TRICOM。这些重组 (r) 痘病毒载体感染专职抗原呈递细胞，这些细胞反过来呈递源自全长 CEA 分子的肽。这些病毒载体还指导三种共刺激分子（B7-1、ICAM-1 和 LFA-3）的表达，每种分子都能够向抗原特异性 T 细胞提供关键的第二激活信号。用牛痘载体引发并用鸡痘载体加强可增强 CEA 特异性 T 细胞反应的形成。 GM-CSF 也在疫苗接种部位给予，因为它促进抗原呈递细胞的激活、成熟和迁移。我们计划评估该疫苗方案与干扰素-α-2b (IFN-a2b) 联合使用时的安全性和有效性。 IFN-a 将与该疫苗方案结合使用，因为它能够快速上调患者肿瘤细胞中的 CEA 表达。此外，IFN-a 上调肿瘤细胞 MHC I 类分子的表达，这些分子对于将肿瘤抗原呈递给溶细胞 T 细胞至关重要。因此，我们假设 IFN-a 治疗会增加患者肿瘤细胞上 CEA 和 MHC I 类的表达，从而导致接种疫苗后抗 CEA 免疫反应得到改善。所有患者将接受 rVaccinia-CEA(6D)-TRICOM 初次疫苗接种，随后每月间隔一次 rFowlpox-CEA(6D)-TRICOM 加强疫苗接种。所有疫苗接种均将从接种当天开始在疫苗接种点皮下注射 GM-CSF（沙格司亭）100 mcg，持续总共 4 天。患者将接受三个皮下注射。每次疫苗接种后注射 IFN-a2b 剂量。治疗的 IFN-a2b 成分将在三名患者的队列中按四个剂量水平（1、3、6 或 900 万单位）进行剂量递增。对肿瘤进行活检和检查，以确定 IFN-a2b 给药对 CEA 和 MHC I 类肿瘤表达的影响。抗 CEA T 细胞反应的形成将通过一组免疫相关研究进行评估。这些分析将使我们能够确定 CEA 肿瘤抗原的表达是否可以通过细胞因子治疗进行调节，以及这是否会转化为改善的抗肿瘤反应。