Recently, gene-based cytokine treatment has been actively pursued as a new promising approach in treating cancer. In an effort to augment the efficiency of antitumor effect by cytokine-mediated immunotherapy, we selected both interleukin (IL)-12 and 4-1BB ligand (4-1BBL) as suitable cytokines to fully activate the type-1 immune response. Coexpression of IL-12 and 4-1BBL mediated by oncolytic adenovirus (Ad) greatly enhanced the antitumor effect. Further, synergistic enhancement in interferon (IFN)-γ levels were seen in mice treated with oncolytic Ad expressing both IL-12 and 4-1BBL. Next, to improve the overall antitumor immune response, we coadministered IL-12-and 4-1BBL-coexpressing oncolytic Ad with dendritic cells (DCs). Combination treatment of IL-12-and 4-1BBL-coexpressing oncolytic Ad and DCs elicited greater antitumor and antimetastatic effects than either treatment alone. Moreover, enhanced type-1 antitumor immune response and higher migratory abilities of DCs in tumors were also observed in the combination arms. The nature of the enhanced antitumor immune response seems to be mediated through the enhanced cytolytic activity of cytotoxic T lymphocytes (CTLs) and IFN-γ-releasing immune cells. Taken together, these data highlight the potential therapeutic benefit of combining IL-12-and 4-1BBL-coexpressing oncolytic Ad with DCs and warrants further evaluation in the clinic.
Bibliographical noteFunding Information:
This work was supported by grants from the Ministry of Commerce Industry and Energy (10030051, C.-O.Y.), the Korea Science and engineering foundation (R04-2004-000-10011-0, R01-2006-000-10084-0, R15-2004-024-02001-0, M10416130002-04N1613-00210, C.-O.Y.), and through its Nuclear Research & Development Program (2007-00299, C.-O.Y.) of the Korea Science and Engineering Foundation. J.-H.H., S.-N.Z., and K.-J.C are graduate students sponsored by the Brain Korea 21 Project for Medical Science, and I.-K.C is a graduate student sponsored by the Graduate Program for Nanomedical Science, Yonsei University College of Medicine, Seoul, South Korea.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Drug Discovery