Glioma regression using gutless adenoviral vectors

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。虽然使用腺病毒递送单纯疱疹病毒1型-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，但向临床应用的过渡仅提供了适度的生存期延长。此外，腺病毒的临床应用受到大多数成人中存在的对腺病毒的预先存在的免疫力的阻碍。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（Flt 3L）腺病毒基因治疗的组合使未免疫动物的存活率达到80%。这种疗法在对腺病毒具有预先存在的免疫力的动物中失败。我们假设使用高容量、无肠腺病毒载体将允许肿瘤消退并延长生存期，即使在存在对腺病毒的预先存在的免疫力的情况下。假设在用TK/Flt 3L处理的动物中观察到的肿瘤消退通过免疫系统的先天性和适应性分支的激活而发生。

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.