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: 7098845
• 负责人: Gwendalyn DiAnn King
• 金额: $ 4.88万
• 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 2008-07-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098845
• 关键词: Adenoviridae; apoptosis; biotechnology; cytotoxic T lymphocyte; ganciclovir; gene therapy; glioblastoma multiforme; herpes simplex virus 1; immune response; immunologic memory; interferon gamma; interleukin 4; laboratory rat; neoplasm /cancer remission /regression; neuroimmunomodulation; neuropathology; neutralizing antibody; nonhuman therapy evaluation; nucleic acid quantitation /detection; phenotype; postdoctoral investigator; protein tyrosine kinase; thymidine kinase; transfection /expression vector; transforming growth factors

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）：胶质瘤是成人原发性脑肿瘤中最常见的亚型。虽然使用腺病毒传递1型单纯疱疹病毒胸苷激酶（TK）的基因治疗在临床前范例中显示出完全的肿瘤消除，但过渡到临床应用仅提供了适度的生存延长。此外，临床上腺病毒的使用受到大多数成年人对腺病毒已有免疫力的阻碍。利用胶质瘤宏观模型，结合条条性细胞毒（TK）和免疫刺激fms样酪氨酸激酶3配体（Flt3L）腺病毒基因治疗在未免疫动物中可获得80%的存活率。这种疗法在预先对腺病毒免疫的动物中无效。我们假设使用高容量、无胆腺病毒载体将允许肿瘤消退并延长生存期，即使存在预先存在的腺病毒免疫。在用TK/Flt3L治疗的动物中观察到的肿瘤消退被假设是通过激活免疫系统的先天和适应性分支而发生的。