Recombinant Immunotherapy for Renal Cell Carcinoma

肾细胞癌的重组免疫疗法

• 批准号: 7227055
• 负责人: Thomas S Griffith
• 金额: $ 25.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227055
• 关键词: Absorbable Gelatin Sponge; Adenovirus Vector; Adult; Adverse effects; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Biological Response Modifiers; Cell Death; Cell Line; Cell surface; Cells; Cessation of life; Collagen; Comparative Study; Complementary DNA; Data; Dendritic Cells; Depsipeptides; Development; Diagnosis; Disease; Disease regression; Dose; Drug Formulations; Effector Cell; Employment; FR 901228; Family; Gene Transfer; Genes; Half-Life; Hand; Health; Histone Deacetylase Inhibitor; Human; Immune; Immune response; Immunity; Immunocompetent; Immunodeficient Mouse; Immunologics; Immunotherapeutic agent; Immunotherapy; Implant; In Situ; In Vitro; Interferons; Laboratories; Ligands; Lymphokine-Activated Killer Cells; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Renal Cell Cancer; Methods; Mind; Multi-Drug Resistance; Mus; Normal Cell; Numbers; P-Glycoprotein; P-Glycoproteins; Patients; Production; Proteins; Protocols documentation; Range; Rate; Recombinant TNF-Related Apoptosis-Inducing Ligand; Recombinants; Regulation; Relative (related person); Renal Cell Carcinoma; Reporting; Resistance; Site; T-Lymphocyte; TNF-related apoptosis-inducing ligand; TNFSF10 gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Transgenes; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor-Infiltrating Lymphocytes; United States; Viral Vector; adenoviral-mediated; antitumor agent; attributable mortality; base; cell killing; cell type; chemotherapy; cytokine; cytotoxic; cytotoxicity; gene delivery system; gene therapy; human TNF protein; immunogenic; immunogenicity; in vivo; member; neoplastic cell; novel; preclinical study; response; transgene expression; tumor; tumor growth; tumor xenograft; viral gene delivery

DESCRIPTION (provided by applicant): Although many agents induce apoptosis, they are commonly associated with side effects that compromise health. TRAIL (TNF-related apoptosis-inducing ligand)/Apo-2L is generating excitement because it induces apoptosis in a wide range of tumor cells but not in normal cells and tissues. Preclinical studies using systemic TRAIL/Apo-2L doses are safe and can suppress tumor growth in vivo. Large amounts of TRAIL/Apo-2L are, however, needed to inhibit tumor formation, primarily because of the short in vivo half-life of the protein. Therefore, an alternative means of delivery may increase the relative activity of TRAIL/Apo-2L such that larger, more established tumors can be eradicated as efficiently as smaller tumors. This year in the U.S. approximately 30,000 new cases of renal cell carcinoma (RCC) will be diagnosed and nearly 12,000 deaths are expected from RCC. Metastatic RCC carries a median survival of 8 months and almost 30% of RCC patients are diagnosed with advanced metastatic disease. Furthermore, RCC is highly resistant to chemotherapy, a possible consequence of its association with the multidrug-resistance P-glycoprotein. RCC is regarded as an immunogenic tumor, with many reports of spontaneous regression and evidence of tumor-specific immune responses being a strong indicator of the immunogenicity of RCC. Thus, immunotherapy is being intensely studied as a treatment for RCC. Unfortunately, the response rates have been poor and significant toxicity reported, limiting the use of immunotherapy in the treatment of RCC. Gene transfer therapy offers new alternatives in the treatment of RCC. Employment of non-replicative viral gene delivery systems is making it possible to administer genes directly into tumors in situ. Previously, we described the cytotoxic activity of recombinant TRAIL/Apo-2L protein against human RCC cell lines, and the development and testing of a recombinant, replication-deficient adenoviral vector encoding the human TRAIL gene (Ad5-TRAIL). Transfer of the TRAIL gene into human tumor cells in vitro and in vivo, using immunodeficient mice, led to the rapid production and expression of TRAIL/Apo-2L protein, and apoptotic death of the tumor cells. However, it remains unknown whether Ad5-TRAIL will inhibit tumor growth in immunocompetent animals, and if the Ad5-TRAIL-induced tumor cell death will activate systemic antitumor immunity. With this in mind, the proposed project will employ a novel adenoviral vector encoding the mouse TRAIL gene (Ad5-mTRAIL) combined with agents to boost systemic immune responses through augmenting antigen presentation and stimulating T cell expansion to develop unique approaches for the treatment of RCC. Specific Aims: (1) Investigate the ability of DC to present antigens derived from apoptotic Renca cells to stimulate antitumor immunity and analyze the effector cells and mechanism of tumor rejection; and (2) Examine the ability of Gelfoam R and depsipeptide (FR901228) to augment Ad5-mTRAIL infectivity and transgene expression, making Ad5-mTRAIL gene transfer therapy more potent.

描述(由申请人提供)：尽管许多药物诱导细胞凋亡，但它们通常与危害健康的副作用有关。肿瘤坏死因子相关的凋亡诱导配体(TRAIL)/Apo-2L可诱导多种肿瘤细胞的凋亡，但不能诱导正常细胞和组织的凋亡，因此TRAIL/Apo-2L引起了人们的兴奋。使用全身TRAIL/Apo-2L剂量的临床前研究是安全的，可以抑制体内肿瘤的生长。然而，需要大量的TRAIL/Apo-2L来抑制肿瘤的形成，主要是因为这种蛋白质在体内的半衰期很短。因此，一种替代的给药方式可能会增加TRAIL/Apo-2L的相对活性，以便更大、更成熟的肿瘤可以像更小的肿瘤一样有效地被根除。今年，美国将诊断出约30,000例新的肾细胞癌(RCC)病例，预计将有近12,000人死于RCC。转移性肾癌的中位生存期为8个月，几乎30%的肾癌患者被诊断为晚期转移性疾病。此外，肾癌对化疗高度耐药，这可能是其与多药耐药P-糖蛋白有关的结果。肾癌被认为是一种免疫原性肿瘤，许多自发消退的报道和肿瘤特异性免疫反应的证据是肾癌免疫原性的强烈指标。因此，免疫治疗作为肾癌的一种治疗方法正在被广泛研究。不幸的是，免疫治疗的应答率很低，而且有明显的毒性报道，限制了免疫疗法在肾癌治疗中的应用。基因转移治疗为肾癌的治疗提供了新的选择。非复制型病毒基因传递系统的使用使将基因直接注入原位肿瘤成为可能。在此之前，我们描述了重组TRAIL/Apo-2L蛋白对人肾癌细胞株的杀伤活性，以及编码人TRAIL基因的重组复制缺陷腺病毒载体(Ad5-TRAIL)的研制和检测。利用免疫缺陷小鼠将TRAIL基因转移到体内外的人肿瘤细胞中，导致TRAIL/Apo-2L蛋白的快速产生和表达，并导致肿瘤细胞的凋亡性死亡。然而，目前尚不清楚Ad5-TRAIL是否会抑制免疫活性动物的肿瘤生长，以及Ad5-TRAIL诱导的肿瘤细胞死亡是否会激活全身抗肿瘤免疫。考虑到这一点，建议的项目将使用编码小鼠TRAIL基因的新腺病毒载体(Ad5-mTRAIL)，并结合药物通过增强抗原递呈和刺激T细胞增殖来增强全身免疫反应，以开发治疗肾癌的独特方法。具体目的：(1)研究DC提呈凋亡的Renca细胞产生的抗原以刺激抗肿瘤免疫的能力，分析肿瘤排斥反应的效应细胞和机制；(2)检测明胶海绵R和去脂肽(FR901228)增强Ad5-mTRAIL的感染性和转基因表达的能力，使Ad5-mTRAIL的基因转移治疗更加有效。