Combinational immunotherapy for established tumors with engineered tumor vaccines and adenovirus-mediated gene transfer

Abstract

There are currently extensive studies relating to cancer vaccines using tumor cells engineered to express immunogenes and cancer gene therapy using adenovirus (AdV)-mediated gene transfer. In this study, a mouse tumor cell line, V_KC_K, was cotransfected with genes coding for tumor necrosis factor-α (TNF-α) and costimulatory B7-1 molecule to enhance immunogenicity. The transfectant cell line V_KC_K-TNF-α/B7-1 showed reduced tumorigenicity and tumor regression. Its inoculation further induced protective immunity; both CD4⁺ and CD8⁺ T cells were involved in the induction phase, whereas only CD8⁺ T cells mediated the effector phase. Susceptible mice bearing V_KC_K tumors developed a T helper type 2-dominant response, whereas resistant mice with V_KC_K-TNF-α/B7-1 tumor regression developed a T helper type 1-dominant response to V_KC_K, indicating that the tumor regression was related to a shift in the cytokine profile of the host from type 2 to type 1. Vaccination of V_KC_K-TNF-α/B7-1 cells inhibited tumor formation derived from a single dose of 3 × 10⁶ V_KC_K cells and eradicated 3-day tumors but not 10-day tumors. AdV-mediated TNF-α gene transfer by intratumoral injection of AdV-TNF-α significantly inhibited tumor growth but failed to eradicate any well-established tumors. However, combinational immunotherapy with vaccination of V_KC_K-TNF-α/B7-1 cells and AdV-mediated TNF-α gene transfer not only significantly inhibited tumor growth but also eradicated 10-day V_KC_K tumors in three of eight mice. Therefore, the present study may be useful not only in understanding the mechanisms responsible for an efficient antitumoral immunity, but also in establishing a more effective immunotherapeutic approach for cancer patients.