The major goal of this proposal is to determine the therapeutic potential a new replication conditional adenovirus vector AdPSAE1/IL-3. This vector system is composed of two transcomplementing adenoviruses that permit selective replication in the prostate and prostate tumors. It is hypothesized to engender a multimodal therapeutic response by establishing a lytic infection in prostate tumor cells, by sensitizing the tumor to the tumoricidal effects of radiation therapy and by enhancing the immune response to endogenous tumor antigens. The purpose of this proposal is to examine these effects in a systematic fashion to allow for the subsequent development of a new treatment modality for patients afflicted with prostate cancer. The key elements of the oncolytic IL-3 viral vector product are two adenoviral vectors which complement each other to permit selective adenoviral replication and tumor cell lysis limited to cancer tissues. The genome of one of these vectors, AdPSAE1/IL-3, contains the adenoviral inverted terminal repeats (ITRs) 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 an E1-deleted vector is also present. The oncolytic effect of the E1 genes is supplemented by IL-3 expression in cells infected by the AdPSAE1/IL-3 vector. We have demonstrated that IL-3 gene therapy sensitizes tumors to the effects of radiation and stimulates anti-tumor immune responses capable of eradicating metastatic disease. IL-3 stimulates antigen presenting cells (macrophages and dendritic cells) required for the generation of systemic anti-tumor immunity. In animal tumor models, the combination of lL-3 cytokine gene therapy with radiotherapy was synergistic resulting in enhanced efficacy of local radiotherapy and generating systemic anti-tumor immunity.
Our complementary adenoviral vector system will be initially applied to prostate cancer, although our goal is to apply this technology to other cancers as well. The vector system will be applicable to a broad range of cancers and will depend on the availability of tissue specific promoters for the particular tumor type. The use of a general promoter to drive E1A expression in the oncolytic vector is being tested and will make a single pair of complementary viruses applicable to many different cancer types.
