Personalizing DNA Cancer Vaccines

Abstract

Recent progress in tumor immunotherapy highlights the important role of the immune system in combating various cancers. Traditionally designed to protect against infectious diseases, vaccines are now being adapted to stimulate immune responses against tumor-specific neoantigens. Both preclinical studies and clinical trials have explored innovative approaches for identifying neoantigens and optimizing vaccine design, advancing the field of personalized oncology. Among these, DNA-based vaccines have become a particularly attractive approach for cancer immunotherapy. This evolution has been driven by improvements in molecular biology techniques, including more precise methods for detecting tumor-specific mutations, computational tools for predicting immunogenic antigens, and novel platforms for delivering nucleic acid vaccines. Personalized DNA vaccines are typically developed through a complex, multi-step process that involves sequencing a patient's tumor, computational analysis to identify potential targets, and custom vaccine production. In this review, we examine the use of both shared tumor antigens and individualized neoantigens in cancer vaccine development. We outline strategies for neoantigen identification that provide insights into tumor-specific alterations. Furthermore, we highlight recent advances in DNA vaccine technologies, address the current limitations facing cancer vaccines, propose strategies to overcome these challenges, and consider key clinical and technical factors for successful implementation.

Keywords: DNA; cancer vaccine; clinical trial; neoantigens; tumor antigens.

Figure 1

Delivery of DNA vaccines. Outside of conventional intramuscular injection, there are four common strategies used to deliver DNA vaccines. 1. Gene gun, which propels DNA-coated particles into the epidermis. 2. Jet injection, which delivers DNA into the intradermal or intramuscular compartments using high-pressured liquid streams. 3. Microneedle patches, which create microchannels in the skin to release DNA into the dermis. 4. Electroporation, which uses brief electrical pulses that enhances DNA uptake by increasing cell membrane permeability after intradermal or intramuscular injection [4,5]. Created in BioRender. Wu, T. (2025) https://BioRender.com/h276moj (Accessed on 26 July 2025).

Figure 2

Pipeline for Personalized Cancer Vaccine Development. 1. Obtain Sample. Tumor tissue or blood is collected from the patient with PBMCs or matched normal tissues as germline controls—the source of genetic material. 2. Identify tumor-specific neoantigens. Subsequently, sequencing and bioinformatics analyses are performed to detect somatic mutations and generate a list of potential neoantigen candidates. Mutation-dependent neoantigens can be detected using variant callers while mutation-independent neoantigens are detected using RiboSeq or immunopeptidomics. 3. Selection of immunogenic neoantigens. Computational tools prioritize neoantigen candidates based on predicted MHC binding, TCR recognition, clonality, and dissimilarity to self. 4. Verification of neoantigen immunogenicity After potential neoantigen candidates are identified, possible peptides are experimentally validated for their ability to activate T cells using TCR activation assays or T cell killing assays. 5. Manufacturing and development of the vaccine product. The selected neoantigens are encoded into a DNA vaccine platform and administered back to the patient. Created in BioRender. Wu, T. (2025) https://BioRender.com/uefdnut (Accessed on 26 July 2025).