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Abstract
Ad.Egr-TNF is a radioinducible adenovector currently in phase 3 trials for inoperable
pancreatic cancer. The combination of Ad.Egr-TNF and ionizing radiation (IR) contributes
to local tumor control through the production of tumor necrosis factor-α (TNFα) in
the tumor microenvironment. Moreover, clinical and preclinical studies with Ad.Egr-TNF/IR
have suggested that this local approach suppresses the growth of distant metastatic
disease; however, the mechanisms responsible for this effect remain unclear. These
studies have been performed in wild-type (WT) and TNFR1,2(-/-) mice to assess the
role of TNFα-induced signaling in the suppression of draining lymph node (DLN) metastases.
The results demonstrate that production of TNFα in the tumor microenvironment induces
expression of interferon (IFNβ). In turn, IFNβ stimulates the production of chemokines
that recruit CD8(+) T cells to the tumor. The results further demonstrate that activation
of tumor antigen-specific CD8(+) CTLs contributes to local antitumor activity and
suppression of DLN metastases. These findings support a model in which treatment of
tumors with Ad.Egr-TNF and IR is mediated by local and distant immune-mediated antitumor
effects that suppress the development of metastases.