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治疗CEA表达的恶性肿瘤的一种令人兴奋的新方法。本试验将采用两种新的抗CEA疫苗：痘苗-CEA(6D)-Tricom和鸡痘-CEA(6D)-Tricom。这些重组(R)痘病毒载体感染专业抗原提呈细胞，而专业抗原提呈细胞又提呈源自全长CEA分子的多肽。这些病毒载体还指导三个共刺激分子(B7-1、ICAM-1和LFA-3)的表达，每个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。用痘苗载体启动和用鸡痘载体增强可增强CEA特异性T细胞反应的形成。GM-CSF也在接种部位注射，因为它促进了抗原提呈细胞的激活、成熟和迁移。我们计划评估联合干扰素-α-2b(干扰素-a2b)的疫苗方案的安全性和有效性。干扰素-a将与这种疫苗方案相结合，因为它能够快速上调患者肿瘤细胞中CEA的表达。此外，干扰素-a上调肿瘤细胞MHC-I类分子的表达，MHC-I类分子是将肿瘤抗原呈递给细胞溶解T细胞的关键。因此，我们假设干扰素-a治疗将增加患者肿瘤细胞上CEA和MHC I类分子的表达，导致接种疫苗后抗CEA免疫反应的改善。所有患者将接受rVaccinia-CEA(6D)-Tricom初始接种，然后每月间隔接受rFowlpox-CEA(6D)-Tricom加强接种。所有疫苗均皮下注射GM-CSF100微克(Sc)。从接种疫苗当天开始在疫苗接种现场，共持续4天。患者将接受三次S.C.每次接种后的干扰素-a2b剂量。在三名患者的队列中，治疗的干扰素-a2b成分将在四个剂量水平(1、3、6或900万单位)上逐步剂量递增。将对肿瘤进行活检和检查，以确定干扰素-a2b对肿瘤CEA和MHC-I类分子表达的影响。抗CEA T细胞应答的形成将通过一组免疫学相关研究来评估。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来调节，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.