CEA BASED VACCINE THERAPY IN PATIENTS WITH ADVANCED CA

描述：（申请人的摘要）作为我们对免疫系统的理解， 我们对有一天能够利用这种力量的期望也在增加 和免疫系统的特异性，并将其用于治疗或 预防恶性肿瘤。到目前为止，只有少数有限的成功， 实现了，但随着新的代理人的发展和提高的能力， 监测免疫反应，我们现在看到一种令人兴奋的， 癌症免疫治疗领域的复兴。申请人的工作重点是 基于CEA的疫苗的开发。CEA在许多常见的 恶性肿瘤;因此，靶向CEA的疫苗将具有非常广泛的 临床实用性和巨大的影响，对生存的一大人口， 患者在过去两年中，申请人进行了两次临床试验， 基于CEA的疫苗试验已证明这些化合物是安全的， 能够产生新的T细胞反应性，该反应性进一步增加， 添加GM-CSF（和可能的IL-2）。最重要的是，申请人是 在癌症患者中积累临床活性的证据，包括 延长癌症消退。新的证据有力地表明， 共刺激分子（B7-1、ICAM-1、LFA-3）与疫苗构建体的结合， CEA基因本身的修饰（6D突变）导致了显着的 这些化合物的临床前活性的改善。这个目标 项目是通过一系列的快速开发这些新的疫苗结构 有效的临床试验，设计与传统的I期和II期 终点，并允许比较 不同的治疗。最后，申请人将确定 最佳疫苗剂量和时间表，证实了细胞因子对 免疫学终点，并确定6D表位的独立影响 和化疗对患者免疫应答的影响。重要 这些试验的转化方面将是开发和验证 一个新的中间终点，循环CEA阳性的定量 患者体内的细胞，以及免疫反应和 临床反应。到目前为止，申请人的经验与第一代 基于CEA的疫苗已经引起了极大的兴奋，但他 对新型疫苗的预期更高。

DESCRIPTION: (Applicant's Abstract) As our understanding of the immune system increases, so do our expectations of one day being able to harness the power and specificity of the immune system and direct it towards the treatment or prevention of malignancies. To date, only a few limited successes have been achieved, but, with the development of newer agents and an improved ability to monitor the immune response, we now see the emergence of an exciting, revitalized field of cancer immunotherapy. The applicant's focus has been on the development of CEA-based vaccines. CEA is expressed on many common malignancies; therefore vaccines targeting CEA would have extremely broad clinical utility and a dramatic impact on the survival of a large population of patients. In the past two years, the applicant has performed two clinical trials of CEA-based vaccines which have proven these compounds to be safe and capable of generating new T cell reactivity which is further increased by the addition of GM-CSF (and possibly IL-2). Most importantly, the applicant is accumulating evidence of clinical activity in patients with cancer including prolonged cancer regressions. New evidence strongly suggests that the addition of costimulatory molecules (B7-1, ICAM-1, LFA-3) to the vaccine constructs and modifications to the CEA gene itself (6D mutation) results in dramatic improvements in the pre-clinical activity of these compounds. The goal of this project is to rapidly develop these new vaccine constructs through a series of efficient clinical trials which are designed with traditional phase I and II endpoints and to allow for comparisons of immunologic endpoints between the different treatments. In the end, the applicant will have determined the optimum vaccine dose and schedule, confirmed the role of cytokines on the immunologic endpoints, and determined the independent impact of the 6D epitope and chemotherapy on the immunologic response in patients. The important translational aspect of these trials will be the development and validation of a novel intermediate endpoint, the quantification of circulating CEA positive cells in patients, and the relationship between this, the immune response, and clinical response. So far, the applicant's experience with the first generation CEA-based vaccines has generated a great deal of excitement, and yet he anticipates even more from the newer vaccine constructs.