Cytokine Delivery By Tumor-Seeking Lymphocytes

肿瘤寻找淋巴细胞的细胞因子传递

• 批准号: 6709079
• 负责人: Per H. Basse
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-02 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709079
• 关键词: Adenoviridae; Retroviridae; biotechnology; chemokine; cytokine; cytotoxic T lymphocyte; gene delivery system; gene expression; gene therapy; genetic transduction; genetically modified animals; interleukin 2; laboratory mouse; lymphocyte; natural killer cells; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer therapy; passive immunization; therapy design /development; transfection /expression vector

DESCRIPTION (provided by applicant): Targeted delivery to tumors of cytokine genes capable of initiating anti-tumor immune responses is a promising approach for cancer therapy. However, success has been limited due to the lack of efficient methods to ensure gene-expression selectively in established tumors. We have recently shown that adoptively transferred, IL2-activated natural killer (A-NK) cells and PHA- and IL-2-stimulated CD8+ T lymphocytes (called T-LAK cells) localize into tumor with impressive selectively. Our goal is to take advantage of this skill, and demonstrate that cytokine gene-transduced, tumor-seeking A-NK and/or T-LAK cells can be used as vehicles for the delivery of anti-cancer cytokines selectively to tumors and to show that this forced cytokine expression in the tumors will lead to strong anti-tumor immune responses. The SPECIFIC AIMS of this 3-year project are to: 1) Demonstrate that A-N K cells can be transduced with adenoviral vectors to produce significant amounts of cytokines; 2) Analyze the ability of cytokine gene-transduced T-LAK and A-NK cells to localize into tumors and to produce cytokines at the tumor site, and; 3) Demonstrate that adoptive transfer of cytokine gene-transduced A-NK and T-LAK cells leads to elimination of tumors without induction of systemic toxicity. To accomplish this, T-LAK and A-NK cells will be adeno- or retro-virally transduced with one or several genes encoding for cytokines/chemokines known to have anti tumor effect via stimulation of either NK cells, DCs, and T helper cells and CTLs, namely IL-2, IL-4, IL12, IL-15, IL-18, IFNg, GM-CSF, RANTES and lymphotactin. The ability of successfully transduced T-LAK and A-NK cells to localize into tumors and to produce cytokine at the tumor site will be tested in animal tumor models. The host response, such as increased accumulation of effector cells into the tumor tissue, induced by the intratumorally produced cytokines, will be measured. The therapeutic potential of this approach will be evaluated by analyzing tumor-reduction resulting from injection of batches of A-NK and/or T-LAK cells, each capable of producing one or several anti-cancer cytokines. The mechanism behind any anti-tumor effect observed, will be elucidated. Depending on the cytokines produced by the tumor-seeking A-NK and T-LAK cells, we anticipate that we can manipulate the host immune system to elicit strong innate and adaptive anti-tumor responses without induction of toxic side effects. On this background, it should be possible to substantially improve the efficacy of tumor-targeted cytokine gene-therapy of cancer.

描述（由申请人提供）：靶向递送能够启动抗肿瘤免疫反应的细胞因子基因是一种很有前途的癌症治疗方法。然而，由于缺乏有效的方法来确保在已建立的肿瘤中选择性地表达基因，成功受到限制。我们最近的研究表明，过继转移、il -2激活的自然杀伤细胞（A-NK）以及PHA和il -2刺激的CD8+ T淋巴细胞（称为T- lak细胞）具有令人印象深刻的选择性定位到肿瘤中。我们的目标是利用这一技能，并证明细胞因子基因转导，肿瘤寻找的A-NK和/或T-LAK细胞可以作为载体，选择性地将抗癌细胞因子传递到肿瘤，并表明这种强迫细胞因子在肿瘤中的表达将导致强烈的抗肿瘤免疫反应。这个为期三年的项目的具体目标是：