Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas

Abstract

Arsenic trioxide (As2O3), a valuable anticancer drug for the treatment of acute promyelocytic leukemia, may also have therapeutic potential for the treatment of solid tumors. However, its therapeutic efficacy against solid tumors is lacking even at high dosages. Other therapeutic strategies are required to enhance the efficacy of As2O3 against solid tumors such as hepatocellular carcinoma (HCC), which is refractory to chemotherapy. B7H3, a new member of the B7 family, has been shown to induce antitumor immunity. Intratumoral injection of B7H3 plasmids eradicates small EL-4 lymphomas, but monotherapy is ineffective against large tumors. Here we investigated whether As2O3 would synergize with B7H3 immunotherapy to combat HCC. Large subcutaneous H22 HCCs (0.7-0.8 cm in diameter) established in BALB/c mice were rapidly and completely eradicated when intratumoral administration of As2Oj was preceded by in situ gene transfer of B7H3. In contrast, neither As2O3 nor B7H3 monotherapy was effective. The antitumor activity of As2O3 was attributed to increased tumor-cell apoptosis, perhaps as a result of direct cytotoxicity as well as decreased tumor angiogenesis. Combination therapy generated potent systemic antitumor immunity mediated by CD8+ and NK cells that was effective in combating a systemic challenge of 1 × 107 parental H22 cells. It led to the simultaneous and complete regression of multiple distant tumor nodules, concomitant with increased levels of serum IFN-γ and cytotoxic T lymphocyte (CTL) activity. In conclusion, combining B7H3-mediated immunotherapy with As2O3 warrants investigation as a therapeutic strategy to combat HCC, and other malignancies. © 2005 Wiley-Liss, Inc.