Limitations of adenovirus-mediated interleukin-2 gene therapy for oral cancer.

Abstract

Adenoviral interleukin-2 (AdV-IL-2) gene therapy has previously not proven effective in treating established murine oral cancer. We hypothesize that the intratumoral level of IL-2 expression is a major limiting factor in treatment outcome. A microscopic disease and established oral cancer murine model was used to test this hypothesis. IL-2 gene transfer was performed with a recombinant adenovirus vector. Tumor cells were transduced in vitro with AdV-IL-2 and subsequently implanted into the floor of the mouth in C3H/HeJ mice. IL-2 expression in vitro ranged from 990 to 1,050 pg/10(6) tumor cells. This microscopic disease treatment resulted in either complete tumor regression or a dramatic decrease in tumor progression. Cytolytic T-cell (CTL) assays demonstrated a predominance of CD8-specific, T-cell-mediated tumor killing. Reducing IL-2 expression by half with a mixture of 1:1 transduced to nontransduced tumor cells eliminated the antitumor effect and decreased the CTL response. These findings support the presence of a critical "threshold" of IL-2 expression. Adenovirus repurification and amplification allowed isolation of a twofold-higher-titer AdV-IL-2 vector. Treatment of established tumors with the higher-titer AdV-IL-2 at a new maximal dose of 1.4 x 10(9) plaque-forming units (pfu) increased in vivo IL-2 expression to 1,127 pg/10(6) cells and generated a significant antitumor response. Complete regression of established tumors, however, could not be achieved, and we noted a decrease in IL-2 expression well below the threshold at 1 week after treatment. Upon repeat maximal AdV-IL-2 injection in vivo, a greater antitumor effect and increased CTL response was seen, but also, 28% of the animals died of IL-2 toxicity. Although limited by expression and toxicity as a single-treatment strategy for established tumors, AdV-IL-2 gene therapy should be considered a potential component of combination therapy strategies.