Glioma regression using gutless adenoviral vectors

使用无肠腺病毒载体进行神经胶质瘤回归

• 批准号: 7259349
• 负责人: Gwendalyn DiAnn King
• 金额: $ 1.98万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2008-02-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259349
• 关键词: Adenovirus Vector; Adenoviruses; Adult; Animals; Antibodies; Apoptosis; Autoimmunity; Biological Models; Brain; Brain Neoplasms; Cells; Cessation of life; Clinical; Clinical Trials; Diagnosis; Disease regression; Ganciclovir; Generations; Glioblastoma; Glioma; Herpesvirus 1; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Interleukin-4; Interphase Cell; Ligands; Mediating; Memory; Microscopic; Modeling; Nervous system structure; Phenotype; Radiosurgery; Rattus; Serum; Testing; Therapeutic; Therapeutic Intervention; Thymidine Kinase; Time; United States; Vascular Endothelial Growth Factor Receptor-1; Viral Vector; brain tissue; chemotherapy; clinical application; clinically relevant; compare effectiveness; cytokine; cytotoxic; day; fetal liver kinase-2; gene therapy; gutless adenoviral vector; human disease; implantation; killings; macrophage; neuropathology; pre-clinical; preclinical study; research study; response; success; transgene expression; tumor; vector; vector genome

DESCRIPTION (provided by applicant): Glioma is the most common subtype of primary brain tumor in adults. While gene therapy using adenoviruses to deliver Herpes Simplex Virus type 1 - thymidine kinase (TK) has shown complete tumor elimination in preclinical paradigms, transition to clinical applications has only provided modest extensions of survival. Additionally use of adenovirus clinically is hampered by pre-existing immunity to adenovirus found in most adults. Utilizing a macroscopic model of glioma, the combination of conditionally cytotoxic (TK) and immune stimulatory FMS-like tyrosine kinase 3 ligand (Flt3L) adenoviral gene therapy results in 80 percent survival in non-immunized animals. This therapy fails in animals with pre-existing immunity to adenovirus. We hypothesize that use of high capacity, gutless adenoviral vectors will allow tumor regression and prolong survival even in the presence of pre-existing immunity to adenovirus. Tumor regression observed in animals treated with TK/Flt3L is hypothesized to occur by activation of innate and adaptive branches of the immune system.

描述（由申请人提供）：神经胶质瘤是成人原发性脑肿瘤最常见的亚型。虽然使用腺病毒传递 1 型单纯疱疹病毒 - 胸苷激酶 (TK) 的基因疗法已在临床前范例中显示出完全消除肿瘤的作用，但向临床应用的过渡仅提供了有限的生存期延长。此外，大多数成年人对腺病毒已有免疫力，这阻碍了腺病毒的临床使用。利用神经胶质瘤的宏观模型，条件性细胞毒性 (TK) 和免疫刺激性 FMS 样酪氨酸激酶 3 配体 (Flt3L) 腺病毒基因疗法的结合使未免疫动物的存活率达到 80%。这种疗法对于已有腺病毒免疫力的动物无效。我们假设，即使在预先存在对腺病毒的免疫力的情况下，使用高容量、无肠腺病毒载体也将使肿瘤消退并延长生存期。推测在用 TK/Flt3L 治疗的动物中观察到的肿瘤消退是通过激活免疫系统的先天性和适应性分支而发生的。

项目成果

Gene therapy and targeted toxins for glioma.

• DOI: 10.2174/156652311795684722
• 发表时间: 2011-06
• 期刊: Current gene therapy
• 影响因子: 3.6
• 作者: Castro MG;Candolfi M;Kroeger K;King GD;Curtin JF;Yagiz K;Mineharu Y;Assi H;Wibowo M;Ghulam Muhammad AK;Foulad D;Puntel M;Lowenstein PR
• 通讯作者: Lowenstein PR