Complementary Adenoviral Vectors for Treatment of Cancer

描述（由申请人提供） 该提议的主要目标是确定复制条件腺病毒载体DuaI-AdIL-3的治疗潜力。该载体系统由两种反式互补腺病毒组成，其允许在前列腺和前列腺肿瘤中选择性复制。其旨在通过在前列腺肿瘤细胞中建立裂解性感染、增强放射治疗的杀肿瘤作用和增强对内源性肿瘤抗原的免疫应答来产生多模式治疗应答。病毒组分之一Max-AdIL-3的基因组含有用于复制的腺病毒反向末端重复序列、腺病毒包装信号、E1基因（其中E1 A在前列腺特异性抗原（PSA）启动子的控制下）和IL-3表达盒。当辅助腺病毒载体也存在时，该载体仅在表达PSA的细胞中繁殖。在动物肿瘤模型中，IL-3细胞因子基因治疗与放射治疗的组合具有协同作用，导致局部放射治疗和全身抗肿瘤免疫的功效增强。在I期SBIR资助的临床前研究中，我们已经表明我们的DuaI-AdIL-3溶瘤载体系统表现出并入载体的溶瘤、免疫增强和辐射增强特性。本II期提案将该项目扩展至临床应用。

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.