LOSS OF TUMORGENICITY INDUCED BY TGF-B ANTISENSE GENE

描述：（申请人摘要）乳腺肿瘤的类乳头状浸润 已被认为是宿主抗肿瘤免疫反应的证据。 的 尽管存在这些免疫细胞，但肿瘤的进展已经被 由于产生免疫抑制物质， 肿瘤内的转化生长因子-β（TGF-β）。 乳腺 癌症患者，肿瘤衍生的TGF-β-1的存在直接 与疾病进展、转移和疾病复发相关。 转化生长因子是一种由多种细胞产生的细胞因子 包括恶性细胞，并且是免疫功能的有效抑制剂。 一 癌症的肿瘤特异性免疫疗法的潜在有效形式是一种 其中肿瘤疫苗由被剥夺了 使用合成TGF-β。 本研究的目的是抑制 通过遗传操作在乳腺肿瘤细胞中产生TGF-β， 使用这些基因修饰的细胞作为疫苗来治疗已建立的肿瘤， 根除残留的转移性疾病。 TGF-β的合成将被阻断 通过在乳腺肿瘤中插入反义TGF-β转录盒， 细胞产生结合内源性信使TGF-β的互补RNA RNA阻止其翻译成蛋白质。 具体目标是 研究的目的是确定：（1a）反义TGF-β肿瘤的疗效 细胞疫苗消除已建立的原发性肿瘤和残留的 转移性疾病 (1b)IFN-γ或B7.1基因转移的能力 提高反义TGF-β肿瘤疫苗的有效性。 (2)的 反义TGF-β基因表达抑制 致瘤性 这项研究的结果将证明， 反义TGF-β肿瘤疫苗在治疗已建立的 肿瘤和根除转移性疾病和IFN-γ的能力， B7.1以增强抗肿瘤活性。 这些研究将导致 开发一种治疗转移性乳腺癌的新的有效方法 癌症的治疗方法，这在临床上有直接的应用。 从长远来看，它 预计这种从基因上消除肿瘤源性 为了引发有效的抗肿瘤反应的免疫抑制将 广泛用于治疗其他形式的癌症。

DESCRIPTION: (Applicant's Abstract) Lymphoid infiltration of mammary tumors has been considered evidence of a host anti-tumor immune response. The progression of tumor despite the presence of these immune cells has been attributed to the production of immunosuppressive substances such as transforming growth factor-beta (TGF-beta) within the tumor. In breast cancer patients, the presence of tumor-derived TGF-beta-1 directly correlates with disease progression, metastases and disease recurrence. Transforming growth factor is a cytokine produced by many cell types including malignant cells and is a potent inhibitor of immune functions. A potentially effective form of tumor-specific immunotherapy of cancer is one in which tumor vaccines consisting of tumor cells deprived of the ability to synthesize TGF-beta are used. The objective of this study is to inhibit the production of TGF-beta in mammary tumor cells by genetic manipulation and to employ these gene modified cells as vaccines to treat established tumors and eradicate residual metastatic disease. TGF-beta synthesis will be blocked by inserting an antisense TGF-beta transcriptional cassette in mammary tumor cells to produce complementary RNA that binds endogenous messenger TGF-beta RNA to prevent its translation to protein. The specific aims of this research are to determine: (1a) The efficacy of antisense TGF-beta tumor cell vaccines in eliminating established primary tumors and residual metastatic disease. (1b) The ability of IFN-gamma or B7.1 gene transfer to improve the effectiveness of antisense TGF-beta tumor vaccines. (2) The mechanism by which antisense TGF-beta gene expression inhibits tumorigenicity. The results from this study will demonstrate the effectiveness of antisense TGF-beta tumor vaccines in treating established tumors and eradicating metastatic disease and the ability of IFN-gamma and B7.1 to potentiate antitumor activity. These studies will lead to the development of a novel and effective approach of treating metastatic breast cancer which has immediate application in the clinic. In the long term, it is expected that this approach of genetically eliminating tumor-derived immunosuppression in order to trigger an effective antitumor response will find widespread use in treating other forms of cancer.