CEA BASED VACCINE THERAPY IN PATIENTS WITH ADVANCED CA

描述：(申请者摘要)作为我们对免疫系统的理解 增长，我们对有一天能够驾驭这股力量的期望也是如此 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，只有少数几个有限的成功 已实现，但随着新代理的开发和能力的提高， 监测免疫反应，我们现在看到一种令人兴奋的， 振兴癌症免疫治疗领域。申请者的重点一直是 以CEA为基础的疫苗的开发。CEA在许多常见的 因此，针对CEA的疫苗将具有极其广泛的 临床实用性和对大量人口生存的巨大影响 病人。在过去的两年里，申请人进行了两次临床 基于CEA的疫苗的试验证明这些化合物是安全的和 能够产生新的T细胞反应性，这种反应性通过 添加GM-CSF(可能还有IL-2)。最重要的是，申请人是 积累癌症患者临床活动的证据包括 长时间的癌症消退。新的证据有力地表明， 共刺激分子(B7-1、ICAM-1、LFA-3)到疫苗构建体和 对CEA基因本身的修饰(6D突变)导致戏剧性的 改善这些化合物的临床前活性。这样做的目的是 该项目是通过一系列的 使用传统的I期和II期设计的高效临床试验 终结点，并允许比较 不同的治疗方法。最终，申请者将决定 最佳疫苗剂量和计划，证实了细胞因子在 免疫终点，并确定6D表位的独立影响 化疗对患者免疫应答的影响。重要的是 这些试验的翻译方面将是开发和验证 一种新的中间终点--循环CEA阳性的定量 患者体内的细胞，以及这与免疫反应和 临床反应。到目前为止，申请者与第一代人的经验 基于CEA的疫苗引起了极大的兴奋，但他 对较新的疫苗结构有更多的期望。

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.