Cellular immunity delimits adenoviral gene therapy strategies for the treatment of neoplastic diseases

Background: Adenoviral gene therapy is a promising new approach for the treatment of neoplastic diseases. To design rational clinical trials and distinguish the effects of therapeutic transgene expression from those caused by viral infection alone, the immune response to the vector must be understood. In these experiments, we further define cellular immunity to recombinant adenovirus. Methods: The immune response to hepatic adenoviral gene transfer was studied in infected mice by depleting T cells with an anti- CD3 antibody, measuring splenocyte cytokine production, determining the impact of transgene expression on inflammation, and assessing liver MHC protein expression. Results: The cellular immune response to recombinant adenovirus is (1) averted by T lymphocyte depletion, (2) marked by a T(H)1 response with increased IL-2 production, (3) directed against both the transgene product and viral proteins, and (4) associated with increased hepatocyte MHC Class I expression. Conclusions: It is necessary to take into consideration the constraints imposed by the immunogenicity of recombinant adenovirus and its transient transgene expression in the clinical application of adenoviral gene transfer for the treatment of cancer.