Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies

Abstract

More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, although immunologically “cold” tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus, have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergise with immunotherapies by turning immunologically “cold” tumours “hot”. Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective “precision virotherapies” that are extensively engineered to prevent off-target up take via native routes of infection and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development

“…Adenoviral vectors are considered to be among the most immunogenic of the viral vector groups, which limits their use for treatment of monogenic disease for in vivo gene therapy [ 50 ]. However, this makes them an excellent choice for use in oncolytic virotherapy [ 51 ] and as a vaccine against, for example, Severe Acute Respiratory Syndrome Coronavirus 2 SARS-Cov2 [ 52 ].…”

Concepts in Oncolytic Adenovirus Therapy

“…It was shown that virus induced oncolysis results in apoptosis, necrosis, necroptosis, pyroptosis, or autophagy that releases signal molecules with a pathogenassociated molecular pattern (PAMP). Infected cells also release damage-associated molecules (DAMP), including HMGB1, heat shock proteins (HSP), intracellular matrix proteins, DNA, ATP, uric acid, or heparin sulphate [51,52]. These molecules stimulate the innate immune response and attract antigen-presenting cells (APCs).…”

“…The released virus progeny further infects the uninfected tumour cells and continues the viral spread. The immunostimulatory molecules released into the TME attract immune cells to the tumour and lead to the activation of both innate and adaptive immunity against the tumour (modified with permission from [52,54]).…”

In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

“…This is particularly relevant to species C adenoviruses, such as human adenovirus type 5 (HAdV-C5), for which neutralizing antibodies have been detected at rates of 30–90% in human populations [ 4 , 5 ], which result in the rapid sequestration and elimination of therapeutics based on HAdV-C5 [ 6 ]. For intravenous applications, HAdV-C5 is also hampered by interactions with host proteins, which result in efficient elimination by the liver and spleen (reviewed in [ 7 , 8 ]). Critical amongst such interactions is the high-affinity, Ca 2+ -dependent interaction between the major adenoviral capsid protein—the hexon—and circulating blood clotting factor X (FX), which results in efficient, heparan sulphate proteoglycan (HSPG)-dependent transduction of liver hepatocytes [ 9 , 10 , 11 ].…”