Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

Abstract

Clinical results with oncolytic adenoviruses (OAds) used as antitumor monotherapies show limited efficacy. To increase OAd potency, transgenes have been inserted into their genome, a strategy known as "arming OAds". Here, we review different parameters that affect the outcome of armed OAds. Recombinant adenovirus used in gene therapy and vaccination have been the basis for the design of armed OAds. Hence, early region 1 (E1) and early region 3 (E3) have been the most commonly used transgene insertion sites, along with partially or complete E3 deletions. Besides transgene location and orientation, transcriptional control elements, transgene function, either virocentric or immunocentric, and even the codons encoding it, greatly impact on transgene levels and virus fitness.

Oncolytic adenovirus with MUC16-BiTE shows enhanced antitumor immune response by reversing the tumor microenvironment in PDX model of ovarian cancer

“… 6–8 Various OAds have been investigated in preclinical and clinical studies and have shown tolerable safety and promising efficacy; 9 , 10 however, the therapeutic effect of OAd monotherapy is limited by the body-mediated antiviral response, and immunosuppressive tumor microenvironment (TME). 11 , 12 …”

The Adenovirus Death Protein – a small membrane protein controls cell lysis and disease

“…Oncolytic HAdV-based vectors were used to investigate the role of HAdV proteins in tumour cell killing, reviewed in [170][171][172][173]. Regarding ADP [29], ADPoverexpressing HAdV mutants were designed for oncolytic therapy.…”

The Role of Adenovirus in Cancer Therapy

“…The collection also includes insightful reviews discussing the important features needed to be considered when expressing transgenes from oncolytic adenoviruses, also known as "arming OAds" [13]. The insertion of therapeutic transgenes into OAds genomes has been the main strategy to improve their therapeutic potential.…”

“…However, one must consider at least four different parameters when designing an armed OAd: transgene location, transcriptional control elements, transgene codon usage, and the transgene itself. For example, they postulated that the E3 insertion site could be beneficial for immunocentric transgenes aiming to stimulate the immune system due to the elimination of E3's inherent functions that are specifically involved in immune evasion [13]. On the other hand, when expressing virocentric transgenes, which aim to improve the oncolytic effect, they suggest expressing these in late transcription sites (L1-4) in non-E3-deleted viruses for a longer persistency [13].…”

“…For example, they postulated that the E3 insertion site could be beneficial for immunocentric transgenes aiming to stimulate the immune system due to the elimination of E3's inherent functions that are specifically involved in immune evasion [13]. On the other hand, when expressing virocentric transgenes, which aim to improve the oncolytic effect, they suggest expressing these in late transcription sites (L1-4) in non-E3-deleted viruses for a longer persistency [13]. Overall, a strategy arming OAds must consider numerous factors including these major factors in order to yield desired outcomes.…”