Recombinant Immunotherapy for Renal Cell Carcinoma

肾细胞癌的重组免疫疗法

• 批准号: 7388918
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388918
• 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）：虽然许多药物可诱导细胞凋亡，但它们通常与损害健康的副作用相关。 TRAIL（TNF 相关凋亡诱导配体）/Apo-2L 之所以令人兴奋，是因为它能诱导多种肿瘤细胞凋亡，但不会诱导正常细胞和组织凋亡。使用全身 TRAIL/Apo-2L 剂量的临床前研究是安全的，并且可以抑制体内肿瘤生长。然而，需要大量的 TRAIL/Apo-2L 来抑制肿瘤形成，主要是因为该蛋白质的体内半衰期较短。因此，另一种递送方式可能会增加 TRAIL/Apo-2L 的相对活性，从而可以像较小的肿瘤一样有效地根除更大、更成熟的肿瘤。今年，美国将诊断出约 30,000 例肾细胞癌 (RCC) 新病例，预计将有近 12,000 人死于 RCC。转移性肾细胞癌的中位生存期为 8 个月，近 30% 的肾细胞癌患者被诊断患有晚期转移性疾病。此外，肾细胞癌对化疗具有高度耐药性，这可能是其与多药耐药性 P-糖蛋白相关的结果。 RCC 被认为是一种免疫原性肿瘤，有许多自发消退的报道，并且肿瘤特异性免疫反应的证据是 RCC 免疫原性的有力指标。因此，免疫疗法作为 RCC 的治疗方法正在得到深入研究。不幸的是，反应率很低，并且报告了显着的毒性，限制了免疫疗法在肾细胞癌治疗中的使用。基因转移疗法为肾细胞癌的治疗提供了新的选择。非复制病毒基因传递系统的使用使得将基因直接原位注入肿瘤成为可能。之前，我们描述了重组 TRAIL/Apo-2L 蛋白针对人 RCC 细胞系的细胞毒活性，以及​​编码人 TRAIL 基因 (Ad5-TRAIL) 的重组复制缺陷型腺病毒载体的开发和测试。使用免疫缺陷小鼠将 TRAIL 基因在体外和体内转移到人类肿瘤细胞中，导致 TRAIL/Apo-2L 蛋白快速产生和表达，并导致肿瘤细胞凋亡。然而，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仍不清楚。考虑到这一点，拟议的项目将采用编码小鼠 TRAIL 基因 (Ad5-mTRAIL) 的新型腺病毒载体，与通过增强抗原呈递和刺激 T 细胞扩增来增强全身免疫反应的药物相结合，从而开发治疗 RCC 的独特方法。具体目的：（1）研究DC提呈凋亡Renca细胞来源的抗原刺激抗肿瘤免疫的能力，分析效应细胞和肿瘤排斥机制； (2) 检查明胶海绵 R 和缩酚肽 (FR901228) 增强 Ad5-mTRAIL 感染性和转基因表达的能力，使 Ad5-mTRAIL 基因转移疗法更有效。