Modulation of Tumor CEA Levels for an Anti-CEA Vaccine

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的抗cea疫苗；牛痘- cea (6D)-TRICOM和水痘- cea (6D)-TRICOM。这些重组(r)痘病毒载体感染专业抗原呈递细胞，这些细胞反过来呈递来自全长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，每一种分子都能够为抗原特异性T细胞提供关键的第二激活信号。牛痘载体的启动和禽痘载体的增强增强了cea特异性T细胞反应的形成。GM-CSF也在疫苗接种部位给予，因为它促进抗原提呈细胞的激活、成熟和迁移。我们计划评估该疫苗方案与干扰素- α -2b （IFN-a2b）联合使用的安全性和有效性。IFN-a将与该疫苗方案联合使用，因为它能够快速上调患者肿瘤细胞中CEA的表达。此外，IFN-a上调肿瘤细胞MHC I类分子的表达，MHC I类分子对于肿瘤抗原向溶细胞T细胞的呈递至关重要。因此，我们假设IFN-a治疗将增加患者肿瘤细胞上CEA和MHC类I的表达，从而在接种疫苗后改善抗CEA免疫反应。所有患者将接受牛痘- cea (6D)-TRICOM的启动疫苗接种，然后每月间隔一次接种rFowlpox-CEA(6D)-TRICOM。所有疫苗接种将在接种当日开始，在疫苗接种部位皮下注射100微克GM-CSF (sargramostim)，持续4天。患者将在每次疫苗接种后接受三毫克剂量的IFN-a2b。治疗的IFN-a2b成分将在3名患者的队列中剂量递增超过4个剂量水平（1,3,600或900万单位）。肿瘤将进行活检和检查，以确定IFN-a2b给药对肿瘤中CEA和MHC i类表达的影响。抗CEA T细胞反应的形成将通过一组免疫学相关研究来评估。这些分析将使我们能够确定细胞因子治疗是否可以调节CEA肿瘤抗原的表达，以及这是否转化为改善的抗肿瘤反应。

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.