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IMPS-19RETROVIRAL REPLICATING VECTOR-MEDIATED DELIVERY OF AN IMMUNODOMINANT NEO-ANTIGEN EPITOPE TARGET FOR VIRO-IMMUNOTHERAPY IN EXPERIMENTAL GLIOMA.

Retroviral replicating vectors (RRV) show intrinsic tropism for actively dividing cells within the immunosuppressed tumor microenvironment, and viral replication significantly enhances transduction efficiency and therapeutic efficacy for cancer gene therapy. RRV-mediated prodrug activator gene therapy is currently being evaluated in clinical trials at multiple centers (www.clinicaltrials.gov, NCT01156584, NCT01470794) with highly encouraging results after local virus injection in patients with recurrent high grade glioma. In murine syngeneic intracranial glioma models, we have shown that RRV-mediated prodrug activator gene therapy can further induce immune responses leading to tumor clearance. We are now investigating the use of RRV for efficient and stable transduction of tumors in situ with an exogenous dominant foreign epitope, thereby "xenogenizing" the tumor. Here we developed a novel RRV displaying the lymphocytic choriomeningitis virus glycoprotein gp33-41 (gp33) epitope fused to the N-terminus of the viral env gene (RRV-gp33). We confirmed that insertion of the gp33 epitope does not affect RRV replication kinetics, genomic stability over serial passage, or transgene expression. In vitro cell viability measured by xCELLigence electrical impedance assay showed target cell-specific cytotoxicity by transgenic lymphocytes engineered with a T cell receptor recognizing the gp33 epitope (P14 cells) when co-cultured with glioma cells transduced with RRV-gp33. In vivo, adoptively transferred P14 cells selectively homed to RRV-gp33-transduced intracranial syngeneic gliomas in immunocompetent hosts, and mediated increased survival. These results indicate that RRV-mediated gene transfer can be effectively used to confer a new antigen to gliomas as a target for subsequent immunotherapy, and further studies are underway to investigate the therapeutic effect of combining RRV-mediated prodrug activator gene therapy and neo-antigen target delivery for adoptive immunotherapy.