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

基本信息

  • 批准号:
    8522171
  • 负责人:
  • 金额:
    $ 17.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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计划,测试新的疫苗平台和策略,结合联合收割机免疫靶向剂,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,李博士将积极开展研究。该研究计划旨在验证以下假设:在转移性PDA患者中,体内免疫应答与临床应答之间存在关联,该患者接受免疫调节剂量的环磷酰胺(Cy)治疗,依次使用引发的同种异体GM-CSF转染的胰腺肿瘤疫苗(GM-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疫苗可提高生存率,这种生存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消耗晚期PDA患者的调节性T细胞诱导更高的亲合力T细胞应答,这也与改善的总存活率(OS)相关。在免疫耐受性癌症,如PDA,组合策略将是必要的,以提高抗肿瘤免疫力。临床前研究表明,在异源初免/加强方案中GM-CSF和基于李斯特菌(Lm)的疫苗的组合导致比单独的任一种试剂更大幅度的T细胞应答的诱导,并且导致上级抗肿瘤应答。Le博士完成了CRS-207的I期试验,CRS-207是一种表达间皮素的Lm减毒活菌株。这种方法通过促进抗原呈递细胞(APC)同时接收适当成熟和有效递送抗原到I类和I类加工途径中所必需的“危险”信号来起作用,同时还刺激先天免疫。CRS-207施用导致间皮素和Lm特异性T细胞应答、细胞因子应答和NK细胞活化的诱导。在I期研究中,17例受试者中有6例存活15个月。这项建议将建立在两种不同但互补的疫苗的临床开发经验的基础上。具体目标是:招募90名标准治疗失败的患有转移性PDA的受试者进入2组研究,该2组研究测试Cy与GM-CSF疫苗的顺序,然后是CRS-207或Cy与单独的GM-CSF疫苗的顺序;评估安全性;测量免疫应答的特异性体内参数如间皮素特异性T细胞应答与临床应答的关联;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。这项建议的成功将对PDA患者产生重大影响。

项目成果

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DUNG T LE其他文献

DUNG T LE的其他文献

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{{ truncateString('DUNG T LE', 18)}}的其他基金

A precision oncology approach to integrating of tumor microenvironment suppressive cell modulators to enhance antitumor immunity
整合肿瘤微环境抑制细胞调节剂以增强抗肿瘤免疫力的精准肿瘤学方法
  • 批准号:
    10408083
  • 财政年份:
    2021
  • 资助金额:
    $ 17.87万
  • 项目类别:
A precision oncology approach to integrating of tumor microenvironment suppressive cell modulators to enhance antitumor immunity
整合肿瘤微环境抑制细胞调节剂以增强抗肿瘤免疫力的精准肿瘤学方法
  • 批准号:
    10661805
  • 财政年份:
    2021
  • 资助金额:
    $ 17.87万
  • 项目类别:
Phase 2 Study of Folfirinox Followed by Ipilimumab/GVAX in Pancreatic Cancer
Folfirinox 继 Ipilimumab/GVAX 治疗胰腺癌的 2 期研究
  • 批准号:
    8616181
  • 财政年份:
    2013
  • 资助金额:
    $ 17.87万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 17.87万
  • 项目类别:
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:
    8700342
  • 财政年份:
    2012
  • 资助金额:
    $ 17.87万
  • 项目类别:

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