Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenicity and growth of established tumor in poorly immunogenic tumor models.

Abstract

Interferon-alpha (IFN-alpha) or CD80 transduction of tumor cells individually reduces tumorigenicity and enhances antitumor responses. Here, we report that the combination of IFN-alpha and CD80 cancer gene therapy in poorly immunogenic murine tumor models, the colorectal adenocarcinoma cell line MC38, and the methylcholanthrene-induced fibrosarcoma cell line MCA205 reduces tumor growth more efficiently without affecting in vitro growth. Wild-type (WT), neomycin-resistance (Neo) gene-, or CD80-transduced tumor cells grew progressively in all immunocompetent mice. In contrast, IFN-alpha-transduced MC38 or MCA205 cells were rejected in 13 of 15 and seven of 15 mice, respectively. Synergistic effects were observed when IFN-alpha- and CD80-transduced tumor cells were mixed and inoculated. These admixed cells were rejected by 14 of 15 (MC38) or seven of 15 mice (MCA205), whereas, a mixture of IFN-alpha and Neo cells or CD80 and Neo cells led to tumors associated with progressive growth. Induction of long-lasting tumor immunity against WT tumor cells was demonstrated by rejection of a subsequent rechallenge in 10 of 13 (MC38) and six of seven (MCA205) tumor-free mice. The therapeutic efficacy with established WT MC38 tumors was shown when mice were treated with a vaccine consisting of repetitive injections of IFN-alpha- and CD80-transduced MC38 cells into the contralateral flank (P < 0.01). This treatment was associated with accumulation of CD4+, CD8+ cells and dendritic cells within the established tumor, demonstrating induction of antitumor immune responses. Combination gene therapy using IFN-alpha and CD80 is an effective immune therapy of cancer and could be considered for clinical trials.