Adenovirus-mediated TNF-α Gene Transfer induces Significant Tumor Regression in Mice

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Abstract
Recombinant adenovirus vectors are highly efficient at in vitro and in vivo gene delivery. The in vitro infection of a mouse colon adenocarcinoma cell line MCA-26 with the adenovirus AdV-LacZ can reach a maximal 75% of infectivity at an MOI of 1000. Intratumoral injection of AdV-LacZ (2X109 pfu) resulted in substantial gene transfer in nearly 70% of MCA-26 tumors. After the in vitro infection of AdV-TNF-α, infected MCA-26 cells showed significant secretion of TNF-α (45 ng/ml/106 cells) in tissue culture. The secretion peaks at day 2 and is diminished at day 4 following the viral infection. Infected MCA-26 tumor cells secreting TNF-α significantly reduced their tumorigenicity in syngeneic BALB/c mice. In mice bearing small tumors, intratumoral injection of 2X109 pfu of AdV-TNF-α virus with a repeated booster treatment resulted in complete regression of three tumors and significant diminution of the other two with a mean tumor-weight of 0.16 g; this is in contrast to 0.85 g and 1.62 g for tumors injected with the control AdV-pLpA and PBS respectively (p<0.01). Mice with complete tumor regression further developed protective immunity against the second challenge of MCA-26 inoculation. In mice bearing large tumors, this treatment also caused significant inhibition of tumor growth with a mean tumor weight of 0.65 g vis-a-vis 3.05 g for tumors injected with the control AdV-pLpA. On the contrary, in mice bearing large tumors, the treatment of tumors with pCI-TNF-α delivered by the gene gun did not induce significant tumor inhibition. These results indicate that the adenoviral delivery of TNF-α gene is more efficient than the particle-mediated gene gun device, and that adenovirus-mediated cytokine gene therapy may be a useful approach in the clinical management of human solid tumors.