IMMUNO GENE THERAPY OF COLON CANCER

描述：（申请人的描述）本提案的目的是 将新型免疫基因疗法的令人鼓舞的临床前结果转化为 结肠癌进入临床环境，并进一步了解 免疫刺激和免疫抑制因子，可能会影响宿主 针对已知和新的肿瘤相关的抗肿瘤免疫应答 抗原（TAAs）。 我们计划研究三种不同类型的 增强治疗性肿瘤细胞功效的遗传操作 疫苗：1）免疫刺激细胞因子IL-2的基因转移; 2） 通过反义载体抑制免疫抑制因子TGF-β;和 3)共刺激分子B7.1-CD 80的表达。 我们最近 在第一个RAC/FDA的背景下启动了拟议的临床分析 获批的结肠癌主动肿瘤免疫治疗的I期试验， IL-2转导的细胞。 在该试验中，患者免疫接种 与自体IL-2转导的混合的自体辐射肿瘤细胞 成纤维细胞 实际考虑要求探索同种异体移植 细胞用于肿瘤免疫治疗，这是最近的支持， 鉴定由许多人表达共有MUC-1，GA 733）和法师TAA 结肠肿瘤和我们将在临床试验中使用的肿瘤细胞系。 我们计划在使用自体细胞进行初步试验后， 使用同种异体肿瘤细胞和同种异体IL-2转导的成纤维细胞。 随后的试验将检查转基因的影响， 同种异体肿瘤细胞抑制TGF-β和表达B7.1的组合 将IL 2转导的成纤维细胞。 不同的疫苗制剂将 在产生抗肿瘤免疫和临床应用方面， 应答 患者外周血和接种部位单核细胞 细胞和衍生的细胞毒性T细胞（CTL）克隆将用于 针对肿瘤细胞组和HLA匹配的细胞毒性测定 用已知的TAA基因转导成纤维细胞以鉴定免疫应答 针对已知的TAAS。 RNA指纹“差异显示” 技术比较肿瘤细胞敏感和不敏感的细胞介导的 细胞毒性将被用于鉴定新的TAA基因。 的信息 从这些研究中获得的信息将确定实用的，转基因的， 适合在临床试验中进一步评价的同种异体肿瘤疫苗 并进一步了解免疫刺激与 和免疫抑制因子产生抗肿瘤免疫， 已知的和新的TAAS。

DESCRIPTION: (Applicant's Description) The objective of this proposal is to translate encouraging pre-clinical results of novel immuno-gene therapies of colon carcinoma into the clinical setting and to further our understanding of immunostimulatory and immunosuppressive factors which may affect host anti-tumor immune responses against known and novel tumor associated antigens (TAAs). We plan to examine the effects of three different types of genetic manipulations to enhance the efficacy of therapeutic tumor cell vaccines: 1) Gene transfer of the immunostimulatory cytokine IL-2; 2) Inhibition of the immunosuppressive factor TGF-b by an antisense vector; and 3) Expression of the co-stimulatory molecule B7.1-CD80. We have recently initiated the proposed clinical analyses in the setting of the first RAC/FDA approved Phase I trial in colon carcinoma of active tumor immunotherapy with IL-2 transduced cells. In this trial, patients are immunized with autologous, irradiated tumor cells mixed with autologous IL-2 transduced fibroblasts. Practical considerations mandate the exploration of allogeneic cells for tumor immunotherapy which is supported by the recent identification of shared MUC-1, GA733 ) and MAGE TAAs expressed by many colon tumors and the tumor cell lines we will employ in our clinical trials. We plan to follow our initial trial using autologous cells with a trial employing allogeneic tumor cells and allogeneic IL-2 transduced fibroblasts. Subsequent trials will examine the effects of genetically modifying the allogeneic tumor cells to inhibit TGF-b and to express B7.1 in combination will IL2 transduced fibroblasts. The different vaccine preparations will be compared with respect to the generation of anti-tumor immune and clinical responses. Patients' peripheral blood and vaccination site mononuclear cells and derived cytotoxic T cell (CTL) clones will be utilized in cytotoxicity assays against panels of tumor cells and HLA matched fibroblasts transduced with known TAA genes to identify immune responses directed against known TAAS. RNA fingerprinting "differential display" techniques comparing tumor cells sensitive and insensitive to cell mediated cytotoxicity will be utilized to identify novel TAA genes. The information obtained from these studies will identify practical, genetically modified allogeneic tumor vaccines suitable for further evaluation in clinical trials and further our understanding of the relationships between immunostimulatory and immunosuppressive factors in generating anti-tumor immunity against known and novel TAAS.