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Cytokine Delivery By Tumor-Seeking Lymphocytes

肿瘤寻找淋巴细胞的细胞因子传递

基本信息

批准号：
7010096
负责人：
Per H. Basse
金额：
$ 22.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-02 至 2008-02-28
项目状态：
已结题

项目摘要

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)：将能够启动抗肿瘤免疫反应的细胞因子基因定向递送到肿瘤是癌症治疗的一种有前途的方法。然而，由于缺乏有效的方法来确保基因在已建立的肿瘤中选择性表达，成功受到了限制。我们最近发现，过继转移的IL-2激活的自然杀伤细胞(A-NK)和PHA和IL-2刺激的CD8+T细胞(称为T-LAK细胞)选择性地定位于肿瘤组织。我们的目标是利用这一技术，证明细胞因子基因转导的寻找肿瘤的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输送到肿瘤，并证明这种强制细胞因子在肿瘤中的表达将导致强大的抗肿瘤免疫反应。这个为期3年的项目的具体目标是： 1)证明腺病毒载体可以转导A-N-K细胞产生大量的细胞因子； 2)分析细胞因子基因转导的T-LAK和A-NK细胞在肿瘤内的定位和在肿瘤部位产生细胞因子的能力； 3)证实过继转移细胞因子基因转导的A-NK和T-LAK细胞可在不引起全身毒性的情况下消除肿瘤。为了达到这一目的，T-LAK和A-NK细胞将被腺病毒或逆转录病毒转导到编码细胞因子/趋化因子的一个或多个基因，这些基因通过刺激NK细胞、DC、T辅助细胞和CTL，即IL-2、IL-4、IL12、IL-15、IL-18、IFNG、GM-CSF、RANTES和淋巴动蛋白而具有抗肿瘤作用。成功转导的T-LAK和A-NK细胞定位于肿瘤并在肿瘤部位产生细胞因子的能力将在动物肿瘤模型中进行测试。将测量宿主的反应，例如由肿瘤内产生的细胞因子诱导的效应细胞在肿瘤组织中的聚集增加。这种方法的治疗潜力将通过分析注射A-NK和/或T-LAK细胞批次产生的肿瘤减少来评估，每个A-NK和/或T-LAK细胞都能够产生一种或几种抗癌细胞因子。所观察到的任何抗肿瘤作用背后的机制将被阐明。根据寻找肿瘤的A-NK和T-LAK细胞产生的细胞因子，我们预计我们可以操纵宿主免疫系统，在不诱导毒副作用的情况下引发强大的先天和适应性抗肿瘤反应。在此背景下，肿瘤靶向细胞因子基因治疗癌症的疗效应该有可能大幅提高。