Intratumoral Administration of Low Doses of an Adenovirus Vector Encoding Tumor Necrosis FactorαTogether with Naive Dendritic Cells Elicits Significant Suppression of Tumor Growth without Toxicity

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Abstract
Although tumor necrosis factor α (TNF-α) is a potent cytokine with a myriad of innate immune antitumor properties, systemic administration of TNF-α is associated with significant toxicity, limiting the use of the TNF-α protein as an antitumor therapeutic. On the basis of the knowledge that dendritic cells (DCs) play a central role in initiating antitumor adaptive immune responses, we hypothesized that intratumoral administration of low doses of an adenovirus encoding TNF-α (AdTNF-α) together with syngeneic DCs would act synergistically to suppress preexisting tumors. As a model, four different tumor cell lines, all resistant in vitro to the TNF-α protein, were implanted in syngeneic mice, and established tumors received intratumor AdTNF-α alone or in combination with DCs. At high doses (109 PFU), AdTNF-α alone suppressed tumor growth, but was associated with systemic toxicity. A 100-fold lower AdTNF-α concentration (107 PFU) or high doses of the control vector AdNull had no systemic toxicity, but also minimal suppression of tumor growth. In contrast, local administration of the low dose (107 PFU) of AdTNF-α in combination with syngeneic DCs (AdTNF-α + DCs) elicited marked tumor suppression without toxicity. Administration of AdTNF-α + DCs into tumors elicited tumor-specific cytotoxic T cells and protected animals against subsequent challenge with the same tumor, suggesting that AdTNF-α + DC therapy induced tumor-specific adaptive immune host responses. Consistent with this concept, studies with syngeneic knockout mice showed that MHC class I molecules on DCs as well as CD8+ T cells were necessary for the antitumor effect of intratumor AdTNF-α + DCs. These data demonstrate that the combination of intratumoral administration of the TNF-α cDNA together with naive DCs can evoke tumor suppression without systemic toxicity, providing a new paradigm for the use of TNF-α as antitumor therapy.

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