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

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.