Therapeutic Tumor Control of HER2 DNA Vaccines Is Achieved by an Alteration of Tumor Cells and Tumor Microenvironment by Gemcitabine and Anti-Gr-1 Ab Treatment in a HER2-Expressing Tumor Model.

Therapeutic control of tumors is challenging as they tend to alter their biological functions and microenvironment. In a CT26/HER2 tumor model, HER2 DNA vaccines and even anti-PD-L1 Abs failed to display antitumor therapeutic activity while inducing Ag-specific cytotoxic T lymphocyte (CTL) activity. To clarify this contradictory finding, we selected tumor cells (CT26/HER2-1) from one tumor-bearing animal in the therapeutic model. CT26/HER2-1 cells behaved similar to wild-type CT26/HER2 cells in their HER2 expression, immune cell stimulation for IFN-γ production, and antitumor immune sensitivity. A similar finding was obtained with additional CT26/HER2-2, -3, -4, -5, and -6 cells from the therapeutic model, suggesting that a lack of antitumor therapeutic activity of HER2 DNA vaccines might be ascribed to a factor in the tumor microenvironment, but not to an alteration in tumor cell functions. When tumor-bearing mice were depleted of myeloid-derived suppressor cells (MDSCs) by anti-Gr-1 Ab treatment, they displayed HER2 vaccine-mediated antitumor activity, suggesting a role of MDSCs in blocking antitumor activity. Moreover, when tumor-bearing mice were treated with gemcitabine, they displayed HER2 vaccine-mediated antitumor activity, suggesting that cytotoxic drug treatment makes tumor cells susceptible to lysis by CTLs. Thus, these studies show that therapeutic control of HER2 DNA vaccines can be achieved by anti-Gr-1 Ab treatment through MDSC depletion and by gemcitabine treatment through sensitization of tumor cells to CTL-mediated killing in this model. These findings may have implications for achieving therapeutic control of CTL-resistant tumors in cancer therapy.

DNA vaccines, electroporation and their applications in cancer treatment.

Numerous animal studies and recent clinical studies have shown that electroporation-delivered DNA vaccines can elicit robust Ag-specific CTL responses and reduce disease severity. However, cancer antigens are generally poorly immunogenic, requiring special conditions for immune response induction. To date, many different approaches have been used to elicit Ag-specific CTL and anti-neoplastic responses to DNA vaccines against cancer. In vivo electroporation is one example, whereas others include DNA manipulation, xenogeneic antigen use, immune stimulatory molecule and immune response regulator application, DNA prime-boost immunization strategy use and different DNA delivery methods. These strategies likely increase the immunogenicity of cancer DNA vaccines, thereby contributing to cancer eradication. However, cancer cells are heterogeneous and might become CTL-resistant. Thus, understanding the CTL resistance mechanism(s) employed by cancer cells is critical to develop counter-measures for this immune escape. In this review, the use of electroporation as a DNA delivery method, the strategies used to enhance the immune responses, the cancer antigens that have been tested, and the escape mechanism(s) used by tumor cells are discussed, with a focus on the progress of clinical trials using cancer DNA vaccines.