Modulation of Tumor CEA Levels for an Anti-CEA Vaccine

描述（由申请方提供）：疫苗接种策略代表了治疗CEA表达恶性肿瘤的一种令人兴奋的新方法。本试验将采用两种新型抗CEA疫苗; Vaccinia-CEA（6D）-TRICOM和Fowlpox-CEA（6D）-TRICOM。这些重组（r）痘病毒载体感染专职抗原呈递细胞，所述专职抗原呈递细胞继而呈递衍生自全长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，每种共刺激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。用牛痘载体引发和用鸡痘载体加强增强CEA特异性T细胞应答的形成。GM-CSF也在疫苗接种部位给予，因为它促进抗原呈递细胞的活化、成熟和迁移。我们计划评估疫苗方案与干扰素-α-2b（IFN-a2 b）联合使用时的安全性和有效性。IFN-a将与该疫苗方案组合，因为其能够快速上调患者肿瘤细胞中的CEA表达。此外，IFN-α上调肿瘤细胞对MHC I类分子的表达，所述MHC I类分子对于将肿瘤抗原呈递给溶细胞性T细胞至关重要。因此，我们假设IFN-α治疗将增加患者肿瘤细胞上的CEA和MHC I类表达，导致疫苗接种后抗CEA免疫应答改善。所有患者将接受rVaccinia-CEA（6D）-TRICOM的初免疫苗接种，然后每月间隔一次接受rFowlpox-CEA（6D）-TRICOM的加强疫苗接种。所有疫苗接种将给予GM-CSF（沙格司亭）100 mcg皮下（s.c.）从接种当天开始，在疫苗接种部位持续4天。患者将接受三次皮下注射。IFN-α 2b的剂量。治疗的IFN-α 2b组分将在三名患者的群组中在四个剂量水平（1、3、6或9百万单位）上剂量递增。将对肿瘤进行活组织检查并检查以确定IFN-α 2b施用对CEA和I类MHC的肿瘤表达的影响。抗CEA T细胞应答的形成将通过一组免疫学相关研究进行评价。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来调节，以及这是否转化为改善的抗肿瘤应答。

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.