DNA-based immunotherapy for cancer: In vivo approaches for recalcitrant targets

Immunotherapy has revolutionized cancer treatment and complements traditional therapies, including surgery, chemotherapy, radiation therapy, and targeted therapies. Immunotherapy redirects the patient's immune system against tumors via several immune-mediated approaches. Over the past few years, therapeutic immunization, which enable the patient's T cells to better recognize and kill tumors, have been increasingly tested in the clinic, with several approaches demonstrating treatment improvements. There has been a renewed interest in cancer vaccines due to advances in tumor antigen identification, immune response optimization, novel adjuvants, next-generation vaccine delivery platforms, and antigen designs. The COVID-19 pandemic accelerated progress in nucleic acid-based vaccine manufacturing, which spurred broader interest in mRNA or plasmid platforms. Enhanced DNA vaccine designs, including optimized leader sequences and RNA and codon optimizations, improved formulations, and delivery via adaptive electroporation using stereotactic intramuscular/intradermal methods have improved T cell responses to plasmid-delivered tumor antigens. Additionally, advancements for direct in vivo delivery of DNA-encoded monospecific/bispecific antibodies offer novel tumor-targeting strategies. This review summarizes the recent clinical data for therapeutic cancer vaccines utilizing the DNA platform, including vaccines targeting common tumor-associated and viral antigens and neoantigen vaccines using nucleic acid technologies. We also summarize preclinical data using DNA-launched monoclonal/bispecific antibodies, underscoring their potential as a novel cancer therapy tool.