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

环磷酰胺改良GM-CSF胰腺肿瘤疫苗李斯特菌-间皮素

• 批准号: 8374057
• 负责人: DUNG T LE
• 金额: $ 17.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374057
• 关键词: Adverse effects; Advisory Committees; Allogenic; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Attention; Attenuated; Attenuated Vaccines; Avidity; CD8B1 gene; Cancer Vaccines; Cells; Clinical; Clinical Data; Combination Drug Therapy; Cyclophosphamide; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Development; Development Plans; Disease; Disease Resistance; Dose; Epitopes; Fostering; Galectin 3; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Immune Targeting; Immune response; Immune system; Immunologics; Immunotherapeutic agent; Immunotherapy; Inflammatory Response; Kinetics; Life; Listeria; Listeria monocytogenes; Liver; Long-Term Survivors; Lung; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of ovary; Measures; Mentors; Mentorship; Mesothelioma; Mononuclear; NK Cell Activation; Natural Immunity; Natural Killer Cells; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phagocytes; Phase; Phase II Clinical Trials; Phenotype; Pre-Clinical Model; Process; Randomized; Recruitment Activity; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Research Proposals; Resected; Safety; Scientist; Signal Transduction; Spleen; T cell response; T-Lymphocyte; Testing; Toxic effect; Training; Translational Research; Tumor Antigens; Tumor Immunity; Tumor Markers; Vaccines; Work; arm; base; cancer type; career development; chemokine; cytokine; didactic education; experience; improved; in vivo; interest; mesothelin; novel strategies; novel vaccines; pancreatic neoplasm; peripheral blood; phase 1 study; preclinical study; programs; response; success; therapy resistant; tumor; two-arm study; uptake

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.

描述（由申请人提供）：本申请的目的是促进 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，她正在开发一项转化研究计划，测试新颖的疫苗平台和策略，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·贾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。职业发展计划将由导师计划、咨询委员会和正式的教学课程组成。此外，乐博士还将积极开展研究。该研究计划旨在检验以下假设：转移性 PDA 患者接受免疫调节剂量的环磷酰胺 (Cy) 治疗后，依次使用引发同种异体 GM-CSF 转染的胰腺肿瘤疫苗 (GM) 进行治疗，体内免疫反应与临床反应之间存在相关性。 -CSF 疫苗），然后使用含有间皮素 (CRS-207) 的李斯特菌 (Lm) 疫苗进行加强。此前，Jaffee 博士在 I 期和 II 期研究中表明，GM-CSF 疫苗可提高存活率，并且这种存活益处与诱导对间皮素（一种 PDA 抗原）具有特异性的 T 细胞相关。此外，免疫调节剂量的 Cy 可以消耗晚期 PDA 患者的调节性 T 细胞，从而诱导更高的亲和力 T 细胞反应，这也与改善总体生存 (OS) 相关。在免疫耐受的癌症中，例如 PDA，需要采取联合策略来提高抗肿瘤免疫力。临床前研究表明，在异源初免/加强方案中组合使用 GM-CSF 和李斯特菌 (Lm) 疫苗可诱导比单独使用任何一种药物更大幅度的 T 细胞反应，并产生优异的抗肿瘤反应。 Le博士完成了CRS-207的I期测试，CRS-207是表达间皮素的Lm减毒活菌株。这种方法的工作原理是促进抗原呈递细胞 (APC) 同时接收适当成熟所需的“危险”信号并将抗原有效递送至 I 类和 I 类处理途径，同时还刺激先天免疫。 CRS-207 给药可诱导间皮素和 Lm 特异性 T 细胞反应、细胞因子反应和 NK 细胞激活。在第一阶段研究中，17 名受试者中有 6 名存活了 15 个月。该提案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 受试者参加一项 2 组研究，依次测试 Cy 和 GM-CSF 疫苗，然后测试 CRS-207 或 Cy 依次使用 GM-CSF 疫苗；评估安全性；测量免疫反应的特定体内参数（例如间皮素特异性 T 细胞反应）与临床反应的关联；并通过评估 OS、反应率和肿瘤标志物动力学来估计临床反应。该提案的成功将对 PDA 患者产生重大影响。