Glioma regression using gutless adenoviral vectors

描述(申请人提供)：胶质瘤是成人最常见的原发脑肿瘤亚型。虽然用腺病毒携带单纯疱疹病毒1型胸苷激酶(TK)的基因治疗在临床前范例中已显示出完全消除肿瘤的作用，但过渡到临床应用仅能适度延长生存期。此外，在大多数成年人中发现的对腺病毒的免疫作用阻碍了腺病毒在临床上的使用。利用胶质瘤的宏观模型，条件细胞毒(TK)和免疫刺激的FMS样酪氨酸激酶3配体(Flt3L)腺病毒基因治疗在未免疫的动物中可导致80%的存活率。这种疗法在对腺病毒已有免疫力的动物身上失败。我们假设，使用高容量、无胆腺病毒载体将允许肿瘤消退和延长生存时间，即使存在对腺病毒的预先存在的免疫。在接受TK/Flt3L治疗的动物中观察到的肿瘤消退被认为是通过激活免疫系统的天然和适应性分支而发生的。

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.