Blockade of TNF-α Decreases Both Inflammation and Efficacy of Intrapulmonary Ad.IFNβ Immunotherapy in an Orthotopic Model of Bronchogenic Lung Cancer

Abstract

Adenoviral immuno-gene therapy using interferon-β has been effective in an orthotopic model of lung cancer. However, pulmonary inflammation induced by adenoviral (Ad) vectors will almost certainly limit the maximally tolerated dose. On the other hand, the strong innate immune response generated by the vector may be helpful in initiating the adaptive immune response required for efficacy. The goals of this study were to develop an effective approach to inhibit Ad.IFNβ-mediated acute pulmonary inflammation and to determine whether this reduction of Ad-mediated inflammation decreased the therapeutic efficacy of Ad.IFNβ in a mouse model of bronchioloalveolar cancer. Our data show that anti-TNF-α antibodies can blunt the innate pulmonary immune response induced by Ad vectors, even in sensitized animals. However, this effect also inhibited the ability of the animal to generate anti-tumor immune responses and reduced survival in an orthotopic lung cancer model responsive to Ad.IFNβ treatment. Interestingly, in a flank model of tumor using a cell line derived from the lung tumor, TNF-α blockade did not inhibit efficacy. These data suggest that the innate immune response to adenovirus in the lung may be important in immuno-gene therapy of lung cancer. Therapeutic application of anti-inflammatory therapy in immuno-gene therapy strategies should thus be undertaken with caution.