DNA vaccine for cancer immunotherapy

Abstract

DNA vaccination has emerged as an attractive immunotherapeutic approach against cancer due to its simplicity, stability, and safety. Results from numerous clinical trials have demonstrated that DNA vaccines are well tolerated by patients and do not trigger major adverse effects. DNA vaccines are also very cost effective and can be administered repeatedly for long-term protection. Despite all the practical advantages, DNA vaccines face challenges in inducing potent antigen specific cellular immune responses as a result of immune tolerance against endogenous self-antigens in tumors. Strategies to enhance immunogenicity of DNA vaccines against self-antigens have been investigated including encoding of xenogeneic versions of antigens, fusion of antigens to molecules that activate T cells or trigger associative recognition, priming with DNA vectors followed by boosting with viral vector, and utilization of immunomodulatory molecules. This review will focus on discussing strategies that circumvent immune tolerance and provide updates on findings from recent clinical trials.

Keywords: APCs, antigen presenting cells; CEA, carcinoembryonic antigen; CIN, cervical intraepithelial neoplasia; CT antigens, cancer-testis antigens; CTLs, cytotoxic lymphocytes; DNA vaccines; DOM, fragment c domain; EP, electroporation; GITR, glucocorticoid-induced tumor necrosis factor receptor family-related genes; HER2, Her2/neu; HSP70, heat shock protein 70; IFNs, interferons; IRF, interferon regulatory factor; Id, idiotype; MHC, major histocompatibility complex; Mam-A, Mammaglobin-A; NHP, non-human primate; PAP, Prostatic acid phosphatase; PMED, particle mediated epidermal delivery; PSMA, prostate-specific membrane antigen; SCT, single-chain trimer; STING, stimulator of interferon genes; TAAs, tumor-associated antigens; TBK1, Tank-binding kinase 1; TLRs, Toll-like receptors; TT, tetanus toxin; Trp2, tyrosinase related protein 2; cellular immune response; hTERT, human telomerase reverse transcriptase; humoral immune response; immune tolerance; phTERT, optimized full-length hTERT; tumor antigens; vaccine delivery.

Figure 1.

Immune activation following DNA Vaccination. Intramuscular administration of DNA vaccine leads to transfection of DNA plasmids encoding antigens mainly in myocytes with some transfection in dendritic cells. DNA sensors such as DAI, H2B, IFI16, DDX41, LRRFIP1, and cGAS are able to detect the presence of dsDNA in the cytosol and induce the activation of STING-TBK1 signaling cascade leading to activation of IRF3 and resulting in expression of Type I IFNs. TLR9 can recognize the unmethylated CpG DNA, which through the signaling of MyD88 activates IRF7 also resulting in expression of Type I IFNs. Dendritic cells can pick up the myocyte-expressed antigens through phagocytosis as they get secreted or released following apoptosis. The antigens are then processed and presented through MHC class I to CD8+ T cells in cross-presentation. Interestingly, this process is promoted by Type I IFNs. Alternatively, dendritic cells can be directly transfected and express the antigens, which then can be presented through MHC class I to CD8+ T cells.