A compendium of adenovirus genetic modifications for enhanced replication, oncolysis, and tumor immunosurveillance in cancer therapy

• Published in: Gene Vol. 679; pp. 11 - 18
• Main Authors: Stepanenko, Aleksei A., Chekhonin, Vladimir P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.12.2018
• Subjects: Adenoviridae; Adenovirus death protein; amino acids; Cancer therapy; Coxsackievirus and adenovirus receptor; Cytotoxic T cells; death; Dicer; E1A protein; E3-19K; Endoplasmic reticulum; epitopes; gene overexpression; genetic engineering; I-leader sequence; Immunotherapy; major histocompatibility complex; Major late promoter; MHCI; MICA/MICB; Minor core protein V; mutation; Natural killer cells; neoplasms; NKG2D; Oncolytic virotherapy; p19 tomato bushy stunt protein; progeny; proteins; RNA interference; SUMOylation; T-lymphocytes; therapeutics; tomatoes; VA RNA; viruses; MICA/MICB; TAP; Ad; MHCI/HLA; E3-19K; MTT; ADP; MLP; NKG2D; E1A protein; Major late promoter; Immunotherapy; Oncolytic virotherapy; p19 tomato bushy stunt protein; Natural killer cells; RISC; SUMO; Dicer; MHCI; I-leader sequence; Coxsackievirus and adenovirus receptor; Adenovirus death protein; VA RNA; CAR; KIR; NKT; PKR; Cancer therapy; Cytotoxic T cells; SUMOylation; NK; Endoplasmic reticulum; Minor core protein V
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2018.08.069

In this review, we specifically focus on genetic modifications of oncolytic adenovirus 5 (Ad5)-based vectors that enhance replication, oncolysis/spread, and virus-mediated tumor immunosurveillance. The finding of negative regulation of minor core protein V by SUMOylation led to the identification of amino acid residues, which when mutated increase adenovirus replication and progeny yield. Suppression of Dicer and/or RNAi pathway with shRNA or p19 tomato bushy stunt protein also results in significant enhancement of adenovirus replication and progeny yield. Truncation mutations in E3-19K or i-leader sequence or overexpression of adenovirus death protein (ADP) potently increase adenovirus progeny release and spread without affecting virus yield. Moreover, E3-19K protein, which was found to inhibit both major histocompatibility complex I (MHCI) and MHC-I chain-related A and B proteins (MICA/MICB) expression on the cell surface, protecting infected cells from T-lymphocyte and natural killer (NK) cell attack, may be tailored to selectively target only MHCI or MICA/MICB, or to lose the ability to downregulate both. At last, E3-19K protein may be exploited to deliver tumor-associated epitopes directly to the endoplasmic reticulum for loading MHCI in the transporter associated with antigen processing (TAP)-deregulated cells. •The mutations in core protein V increase adenovirus replication and progeny yield.•A downregulation of Dicer and/or RNAi pathway enhances replication and progeny yield.•The truncation mutations in E3-19K protein increase release of adenovirus progeny.•A truncation mutation in i-leader sequence increases release of adenovirus progeny.•The E3-19K protein may be tailored to selectively downregulate only MHCI or MICA/MICB.