Complementary Adenoviral Vectors for Treatment of Cancer

描述(由申请人提供) 这项建议的主要目的是确定复制条件型腺病毒载体DuaI-AdlL-3的治疗潜力。该载体系统由两个互补型腺病毒组成，允许在前列腺癌和前列腺癌中选择性复制。它旨在通过在前列腺肿瘤细胞中建立裂解感染，增强放射治疗的杀瘤效果，并通过增强对内源性肿瘤抗原的免疫反应来产生多模式的治疗反应。其中一个病毒成分Max-AdlL-3的基因组包含用于复制的腺病毒反向末端重复序列、腺病毒包装信号、前列腺特异性抗原(PSA)启动子控制下的带有E1a的E1基因，以及IL-3表达盒。这种载体只有在辅助腺病毒载体存在的情况下才能在表达PSA的细胞中传播。在动物肿瘤模型中，IL-3细胞因子基因治疗与放射治疗具有协同作用，可增强局部放射治疗的疗效和全身抗肿瘤免疫。在第一阶段SBIR赠款的临床前研究中，我们已经证明了我们的DuAI-AdlL-3溶瘤载体系统具有融合到载体中的溶瘤、免疫增强和辐射增强特性。这项第二阶段的提案将把该项目扩展到临床应用。

DESCRIPTION (provided by applicant) The major goal of this proposal is to determine the therapeutic potential of a replication conditional adenovirus vector, DuaI-AdlL-3. This vector system is composed of two transcomplementing adenoviruses that permit selective replication in the prostate and prostate tumors. It is designed to engender a multimodal therapeutic response by establishing a lytic infection in prostate tumor cells by enhancing the tumoricidal effects of radiation therapy and by enhancing the immune response to endogenous tumor antigens. The genome of one of the viral components, Max-AdlL-3, contains the adenoviral-inverted terminal repeats for replication, the adenoviral packaging signal, the E1 genes with E1A under the control of a prostate specific antigen (PSA) promoter, and an IL-3 expression cassette. This vector propagates only in cells that express PSA when the helper adenoviral vector is also present. In animal tumor models, the combination of IL-3 cytokine gene therapy with radiotherapy was synergistic, resulting in enhanced efficacy of local radiotherapy and systemic anti-tumor immunity. In the preclinical studies of the Phase I SBIR grant we have shown our DuaI-AdlL-3 oncolytic vector system exhibits the oncolytic, immunity enhancing, and radiation-enhancing properties incorporated into the vector. This Phase II proposal will extend this project to clinical application.