Injection of Delta-24-RGDOX, an oncolytic adenovirus that expresses OX40L on the surface of infected cells, into primary subcutaneous (s.c.) melanoma tumors in mice inhibited the growth of treated s.c. and untreated distant s.c. or intracranial tumors, prolonged survival, and protected against rechallenge. The treatment activated and increased the number of CD8+ and CD4+ T cells in the injected tumor, periphery, and lymphoid organs; decreased the frequency of Tregs and exhausted CD8+ and CD4+ T cells in injected and untreated tumors; and mediated the migration of antigen-specific CD8+ T cells from injected tumors to distant antigen-expressing tumors.
PURPOSE: Intratumoral injection of oncolytic adenovirus Delta-24-RGDOX induces efficacious anti-glioma immunity in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas. EXPERIMENTAL DESIGN: We tested the therapeutic effect of injecting Delta-24-RGDOX into primary subcutaneous (s.c.) B16-Red-FLuc tumors in s.c./s.c. and s.c./intracranial (i.c.) melanoma models in C57BL/6 mice. Tumor growth and in vivo luciferase-expressing ovalbumin-specific (OT-I/Luc) T cells were monitored with bioluminescence imaging. Cells were profiled for surface markers with flow cytometry. RESULTS: In both s.c./s.c. and s.c./i.c. models, 3 injections of Delta-24-RGDOX significantly inhibited the growth of both the virus-injected s.c. tumor and untreated distant s.c. and i.c. tumors, thereby prolonging survival. The surviving mice were protected from rechallenging with the same tumor cells. The virus treatment increased the presence of T cells and the frequency of effector T cells in the virus-injected tumor and mediated the same changes in T cells from peripheral blood, spleen, and brain hemispheres with untreated tumor. Moreover, Delta-24-RGDOX decreased the numbers of exhausted T cells and regulatory T cells in the virus-injected and untreated tumors. Consequently, the virus promoted the in situ expansion of tumor-specific T cells and their migration to tumors expressing the target antigen. CONCLUSIONS: Localized intratumoral injection of Delta-24-RGDOX induces an in situ antovaccination of the treated melanoma, the effect of which changes the immune landscape of the treated mice, resulting in systemic immunity against disseminated s.c. and i.c. tumors.