Cyclophosphamide modified GM-CSF pancreatic tumor vaccine + listeria-mesothelin

描述（由申请人提供）：本申请旨在促进Dung Le博士的职业发展。Le博士的主要兴趣是胃肠道癌症的免疫治疗。具体来说，她正在开发一个转化研究项目，测试新的疫苗平台和策略，结合免疫靶向药物来训练免疫系统识别和攻击癌症。伊丽莎白·杰菲博士将担任她的主要导师。Jaffee博士在胰腺腺癌（PDA）免疫治疗研究方面的丰富经验使她成为理想的导师。职业发展计划将由指导计划、咨询委员会和正式的教学课程组成。此外，乐博士将积极开展研究。该研究计划旨在验证转移性PDA患者体内免疫应答和临床应答之间存在关联的假设，这些患者依次接受免疫调节剂量的环磷酰胺（Cy）和启动异体GM-CSF转染的胰腺肿瘤疫苗（GM-CSF疫苗），然后用含有间皮素（CRS-207）的李斯特菌（Lm）疫苗增强治疗。此前，Jaffee博士在I期和II期研究中表明，GM-CSF疫苗提高了生存率，这种生存率与诱导间皮素（一种PDA抗原）特异性T细胞相关。此外，在晚期PDA患者中，免疫调节剂量的Cy消耗调节性T细胞可诱导更高的贪婪T细胞反应，这也与改善的总生存期（OS）有关。在免疫耐受癌症，如PDA，联合策略将是必要的，以提高抗肿瘤免疫。临床前研究表明，GM-CSF和基于李斯特菌（Lm）的疫苗在异源启动/增强方案中联合使用，诱导的T细胞反应比单独使用任何一种药物都要大，并且具有更好的抗肿瘤反应。Le博士完成了CRS-207的一期试验，这是一种表达间皮素的Lm活减毒株。这种方法的工作原理是促进抗原提呈细胞（apc）同时接收“危险”信号，这是将抗原适当成熟和有效地递送到I类和I类加工途径所必需的，同时也刺激先天免疫。CRS-207可诱导间皮素和lm特异性T细胞反应、细胞因子反应和NK细胞活化。在I期研究中，17名受试者中有6名存活了15个月。这一建议将以两种不同但互补的疫苗的临床开发经验为基础。具体目标是：招募90名标准治疗失败的转移性PDA患者，进行两组研究，先用GM-CSF疫苗检测Cy序列，再用CRS-207或单独用GM-CSF疫苗检测Cy序列；安全评估；测量体内免疫反应的特异性参数，如间皮素特异性T细胞反应与临床反应的关系；并通过评估OS、反应率和肿瘤标志物动力学来评估临床反应。该建议的成功将对PDA患者产生重大影响。

DESCRIPTION (provided by applicant): The purpose of this application is to foster the career development of Dr. Dung Le. Dr. Le's primary interest is in immunotherapy for gastrointestinal cancers. Specifically, she is developing a translational research program testing novel vaccine platforms and strategies that combine immune targeted agents to train the immune system to recognize and attack cancers. Dr. Elizabeth Jaffee will serve as her primary mentor. Dr. Jaffee's depth of experience in pancreatic adenocarcinoma (PDA) immunotherapy research makes her an ideal mentor. The career development plan will be composed of a mentorship plan, an advisory committee, and a formal didactic curriculum. In addition, Dr. Le will be actively conducting research. The research proposal aims to test the hypothesis that there is an association between in vivo immune responses and clinical responses in patients with metastatic PDA treated with immunomodulatory doses of cyclophosphamide (Cy) in sequence with a priming allogeneic GM-CSF transfected pancreatic tumor vaccine (GM-CSF vaccine) followed by boosting with a Listeria (Lm) vaccine containing mesothelin (CRS-207). Previously, Dr. Jaffee has shown in phase I and II studies that the GM-CSF vaccine enhances survival and this survival benefit correlates with the induction of T cells specific for mesothelin, a PDA antigen. In addition, immune modulating doses of Cy to deplete regulatory T cells in patients with advanced PDA induces higher avidity T cell responses which are also associated with improved overall survival (OS). In immune tolerant cancers, such as PDA, combination strategies will be necessary to improve anti-tumor immunity. Pre-clinical studies demonstrate that the combination of GM-CSF and Listeria (Lm)-based vaccines in a heterologous prime/boost regimen results in the induction of T cell responses of greater magnitude than either agent alone, and in superior anti-tumor responses. Dr. Le completed the phase I testing of CRS-207 which is a live-attenuated strain of Lm that expresses mesothelin. This approach works by facilitating antigen presenting cells (APCs) to simultaneously receive the "danger" signals necessary for proper maturation and efficient delivery of the antigen into both class I and class I processing pathways, while also stimulating innate immunity. CRS-207 administration results in the induction of mesothelin and Lm-specific T cell responses, cytokine responses, and NK cell activation. In the phase I study, 6 of 17 subjects survived for e 15 months. This proposal will build on experiences with the clinical development of two distinct, but complementary vaccines. The specific aims are to: recruit 90 subjects with metastatic PDA who have failed standard therapy into a 2 arm study testing Cy in sequence with a GM-CSF vaccine followed by CRS-207 or Cy in sequence with a GM-CSF vaccine alone; assess for safety; measure the association of specific in vivo parameters of immune response such as mesothelin-specific T cell responses with clinical responses; and estimate clinical responses by assessing OS, response rate, and tumor marker kinetics. The success of this proposal would have a significant impact on patients with PDA.