Cytokine Gene Therapy of Residual Leukemia

描述：(申请者摘要)我们的长期目标是开发小说 专门针对并摧毁残留白血病的生物疗法。这个 拟议的研究将检验一个普遍的假设，即定位基因 使用造血祖细胞治疗，基因改造为分泌 人肿瘤坏死因子-α(hTNF-a)，将显著增加 大剂量化疗后残留白血病细胞的破坏/骨 骨髓移植。我们的初步数据显示， 环磷酰胺化疗后人肿瘤坏死因子-a分泌祖细胞 (Cy)和骨髓移植显著提高了小鼠的存活率(80%) 接种致死剂量的32Dp210小鼠髓系白血病细胞 毒副作用。我们将检验与环磷酰胺联合治疗的假设， 骨髓移植，分泌肿瘤坏死因子-α的祖细胞产生更大的 抗白血病的效果比任何方式单独产生的效果都要好。我们将完成 具体目标如下：1)确定在何种程度上 环磷酰胺对辅助性T细胞和细胞毒效应的免疫调节作用 细胞(CTL和NK细胞)参与抗白血病活性 Cy/肿瘤坏死因子-α基因治疗，2)确定骨髓移植中的细胞群(S) (例如，T细胞、间充质细胞或祖细胞)增强 综合治疗的疗效，以及3)确定补肾益气汤的作用机制(S) 环磷酰胺/肿瘤坏死因子-α治疗的抗白血病作用包括：a)增强白血病 树突状细胞的抗原提呈，b)产生白血病特异性 (CTL)和非特异性(NK细胞/巨噬细胞)细胞毒效应细胞，c) 产生具有抗白血病活性的次级细胞因子，以及d) 在白血病细胞中诱导程序性细胞死亡(凋亡)。 这些研究的结果将证明结合这部小说的价值 肿瘤坏死因子α基因与其他常用抗癌药物联合应用的研究进展 治疗策略，以实现最大限度地摧毁残留白血病。这 将使这一新的治疗策略的快速实施成为可能 根除人类残留白血病，而不会产生毒副作用 全身性肿瘤坏死因子-a疗法。

DESCRIPTION: (Applicant's Abstract) Our long-term goal is to develop novel biotherapies that will specifically target and destroy residual leukemia. The proposed studies will test the general hypothesis that site-directed gene therapy with hematopoietic progenitor cells, genetically modified to secrete human tumor necrosis factor-alpha (hTNF-a), will significantly increase the destruction of leukemia cells remaining after high-dose chemotherapy/bone marrow (BM) transplantation. Our preliminary data show that administration of hTNF-a secreting progenitor cells following chemotherapy with cyclophosphamide (CY) and BM transplantation dramatically enhances survival (80 percent) of mice inoculated with a lethal dose of 32Dp210 murine myeloid leukemia cells without toxic side effects. We will test the hypothesis that combined therapy with CY, BM-transplant, and TNF-a secreting progenitor cells generates a greater antileukemic effect than is produced by any modality alone. We will accomplish this by the following specific aims: 1) determine the extent to which immunomodulatory effects of CY on T-helper (Th) cells and cytotoxic effector cells (CTLs and NK cells) contribute toward the antileukemic activity of CY/TNF-a gene therapy, 2) identify the cell population(s) within BM-transplant (e.g., T cells, mesenchymal cells or progenitor cells) that enhances the efficacy of combined therapy, and 3) determine whether the mechanism(s) of the antileukemic effect of CY/TNF-a treatment involves: a) augmentation of leukemia antigen presentation by dendritic cells, b) generation of leukemia specific (CTLs) and non-specific (NK cells/macrophages) cytotoxic effector cells, c) production of secondary cytokines with antileukemic activity, and d) the induction of programmed cell death (apoptosis) in leukemia cells. The results of these studies will demonstrate the value of combining this novel approach of site-directed TNFa gene therapy with other commonly used anticancer treatment strategies to achieve maximum destruction of residual leukemia. This would make possible the rapid implementation of this novel treatment strategy to eradicate residual leukemia in humans, without the toxic side effects of systemic TNF-a therapy.