雷帕霉素和 IL-21 条件 CD8 T 细胞用于 Ov 过继细胞治疗-猫眼课题宝

雷帕霉素和 IL-21 条件 CD8 T 细胞用于 Ov 过继细胞治疗

批准号：

8754345

负责人：

Protul Shrikant

金额：

$58.69万

依托单位：

ROSWELL PARK CANCER INSTITUTE CORP

依托单位国家：

美国

项目类别：

财政年份：

资助国家：

美国

项目状态：

未结题

起止时间：

至

来源：

https://reporter.nih.gov/project-details/8754345

关键词：

Active Immunization Adoptive Cell Transfers Affect Antigens Avidity CD4 Positive T Lymphocytes CD58 gene CD80 gene CD8B1 gene CTAG1 gene Cancer Patient Cancer Remission Cell Therapy Cells Clinical Trials Dendritic Cells Disease remission Dose Effector Cell Environment Epithelial ovarian cancer Frequencies Generations Goals Human IL2RA gene Immune Immunity Immunization Immunotherapy Intercellular adhesion molecule 1 Kynurenine Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory Methods Modeling Mus Outcome Patients Peptides Phase Phase I Clinical Trials Phase II Clinical Trials Phenotype Poxviridae Proteins Randomized Recombinants Regimen Regulation Regulatory T-Lymphocyte Reporting Safety Shapes Sirolimus Specificity T cell response T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Toxic effect Triad Acrylic Resin Tryptophan Tumor Antigens Tumor-Infiltrating Lymphocytes University of Pittsburgh Cancer Institute Vaccinated Vaccination Vaccines WT1 gene base clinical efficacy combinatorial cytokine design enzyme activity in vivo inhibitor/antagonist mTOR Inhibitor neoplastic cell novel novel strategies ovarian neoplasm phase 1 study prognostic response tumor tumor growth vaccine efficacy vaccine evaluation

中文摘要

翻译

免疫疗法是延长卵巢癌缓解率的一种有吸引力的选择。使用过继性细胞转移（ACT）离体产生的肿瘤抗原特异性效应/记忆CD 8 + T细胞绕过了卵巢癌患者中存在的调节环境，并且可以介导持久的免疫。然而，离体产生效应/记忆CD 8 + T细胞的策略尚未被描述，ACT治疗卵巢肿瘤的应用仍然未经测试。基于我们报告的发现和使用鼠和人T细胞产生的新证据，我们假设γ链细胞因子IL-21与mTOR抑制剂雷帕霉素组合将离体产生肿瘤抗原特异性效应/记忆CD 8 + T细胞，其通过ACT使卵巢癌患者具有持久免疫力。我们设计了两个具体目标来检验假设，并生成可以支持2期试验的信息。首先，确定雷帕霉素和IL-21的组合剂量，其最佳地产生具有高复制潜力的人WT 1特异性效应/记忆CD 8 + T细胞，用于过继细胞治疗，其次，在I期研究中评估IL-21/雷帕霉素调节的WT-1特异性CD 8 + T细胞过继转移至晚期卵巢癌患者的安全性、体内持久性和抗肿瘤功效。这项研究的完成将确定一种新的策略来产生用于效应/记忆功能的抗原特异性CD 8 + T细胞，并测试它们在ACT中的功效，很可能建立一种治疗卵巢癌的新方法。

英文摘要

Immunotherapy is an attractive option to extend remission rates in ovarian cancer. The use of adoptive cell transfer (ACT) of ex vivo generated tumor-antigen specific effector/memory CD8+ T cells circumvents the regulatory environment present in ovarian cancer patients and can mediate durable immunity. However, strategies to ex vivo generate effector/memory CD8+ T cells have not been described and the application of ACT to treat ovarian tumor remains untested. Based on our reported findings and new evidence generated by using both murine and human T cells, we hypothesize that the gamma chain cytokine; IL-21 in combination with mTOR inhibitor; rapamycin, will ex vivo generate tumor-antigen specific effector/memory CD8+ T cells that enable durable immunity to ovarian cancer patients by ACT. We have designed two specific aims to test the hypothesis and generate information that can support a phase 2 trial. First, to determine the combinatorial dose of Rapamycin and IL-21 that optimally produces human WT1 specific effector/memory CD8+ T cells with high replicative potential for adoptive cellular therapy and second to evaluate in a Phase I study, the safety, in vivo persistence and anti-tumor efficacy of IL-21/ Rapamycin conditioned WT-1 specific CD8+ T cells adoptively transferred to patients with advanced ovarian cancer. The completion of this study will identify a new strategy to generate antigen-specific CD8+ T cells for effector/memory function and test their efficacy in ACT, it is likely to establish a new approach to treat ovarian cancer.

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