Immunization by Direct DNA Inoculation Induces Rejection of Tumor Cell Challenge

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Abstract
Direct DNA inoculation is the basis for a new technology that has been successfully used for in vivo induction of both humoral and cellular immune responses. However, the immunological parameters of this new approach remain to be evaluated in detail. We report here that direct DNA inoculation can induce protection from malignant tumor cell challenge through the generation of specific immune responses directed against antigens displayed on the tumor cells. The protected mice remain tumor-free for more than 1 year post-challenge. Memory responses upon tumor rechallenge were observed for both humoral and cellular immunity. Inoculated animals were able to reject otherwise lethal tumors several months following the original DNA inoculation protocol. These in vivo protective responses suggest that further analysis of this technology for vaccine development or immune therapeutic strategies is warranted. Using a variety of delivery methods, DNA constructs inoculated directly into animals have been shown to generate host immunity against influenza virus, human immunodeficiency virus type 1 (HIV-1), bovine hepatitis virus, human hepatitis B surface antigen, human T lymphotrophic virus type I (HTLV-I), rabies, malaria, and human immunoglobulin V regions. It is possible that direct inoculation of a tumor-associated antigen (TAA) gene may induce antitumor cell responses that will protect host animals from tumor cell progression. In this report, we analyze a DNA inoculation procedure using a live challenge system for in vivo testing of anticellular immune responses. Syngenic lethal tumor cells were “marked” to display the relevant immunologic target antigen. Using this model, we demonstrate that DNA inoculation can induce protection from lethal challenge by mounting an antigen-specific immune responses against a model tumor antigen. We observed that such immune responses induce memory at both the humoral as well as cellular level, i.e., in particular cytotoxic T-cell responses, and that the induced responses appear superior to immunization with recombinant protein antigen. There appears to be a temporal nature to the immune response with multiple immunizations increasing protection. Additional vaccination studies using this methodology, as well as human disease protection strategies using direct DNA inoculation as a putative vaccine or as an immunotherapy, are under consideration.