LOSS OF TUMORGENICITY INDUCED BY TGF-B ANTISENSE GENE

描述：(申请人摘要)乳腺肿瘤的淋巴浸润性 已经被认为是宿主抗肿瘤免疫反应的证据。这个 尽管存在这些免疫细胞，但肿瘤的进展 归因于免疫抑制物质的产生 肿瘤组织中转化生长因子-β(TGF-β)的表达。在胸前 肿瘤患者体内直接存在肿瘤来源的转化生长因子-β1 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 包括恶性肿瘤细胞，是一种有效的免疫功能抑制物。一个 肿瘤特异性免疫治疗的潜在有效形式是一种 其中由肿瘤细胞组成的肿瘤疫苗被剥夺了 合成转化生长因子-β。这项研究的目的是抑制 基因操作在乳腺肿瘤细胞中产生转化生长因子-β的研究 使用这些基因修饰的细胞作为疫苗来治疗已建立的肿瘤和 根除残留的转移性疾病。转化生长因子-β的合成将被阻止 在乳腺肿瘤中插入反义转化生长因子-β转录盒 细胞产生与内源性信使转化生长因子-β结合的互补RNA 阻止其转化为蛋白质的RNA。这样做的具体目的是 研究目的是确定：(1)反义转化生长因子-β肿瘤的疗效 细胞疫苗在消除已建立的原发肿瘤和残留物中的作用 转移性疾病。(1B)干扰素-γ或B7.1基因转移的能力 提高反义转化生长因子-β肿瘤疫苗的有效性。(2) 反义转化生长因子-β基因表达抑制机制的研究 致瘤性。这项研究的结果将证明 反义转化生长因子-β肿瘤疫苗对已确诊患者的治疗作用 肿瘤与根治转移性疾病及干扰素-γ和 B7.1增强抗肿瘤活性。这些研究将导致 一种治疗转移性乳腺肿瘤的新方法的发展 可立即应用于临床的癌症。从长远来看，它 预计这种从基因上消除肿瘤来源的方法 为了触发有效的抗肿瘤反应，免疫抑制将 被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.