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SMARTmid™ DNA vectors have been designed to be a DNA-based delivery system that can directly enhance the immune system via CD8+ and CD4+ lymphocytes that will then lead to tumor load reductions or the prevention of tumor recurrence. Pre-clinical studies of SMARTmid™ vectors along with anti-PD-L1 and/or anti-CTL4 is undergoing testing to demonstrate the potential to initiate a systemic immune response that can be lead decrease toxicities of current chemotherapies. In addition, SMARTmid™ vectors in conjunction with anti-PD-L1 and/or anti-CTL4 can be used as a standalone treatment for many tumors that express the protein antigens, like MAGE A. The second-generation SMARTmid™ vectors will incorporate DNA localization properties to enhance uptake into the nucleus and magnify protein expression. The fully synthetic method for producing SMARTmid™ DNA vectors for mammalian cell transduction is a powerful template in which to build an immunotherapy for the treatment of MAGE-A antigen expressing tumors.