Non-Human Primate-Derived Adenoviruses for Future Use as Oncolytic Agents?

Abstract

<jats:p>Non-human primate (NHP)-derived adenoviruses have formed a valuable alternative for the use of human adenoviruses in vaccine development and gene therapy strategies by virtue of the low seroprevalence of neutralizing immunity in the human population. The more recent use of several human adenoviruses as oncolytic agents has exhibited excellent safety profiles and firm evidence of clinical efficacy. This proffers the question whether NHP-derived adenoviruses could also be employed for viral oncolysis in human patients. While vaccine vectors are conventionally made as replication-defective vectors, in oncolytic applications replication-competent viruses are used. The data on NHP-derived adenoviral vectors obtained from vaccination studies can only partially support the suitability of NHP-derived adenoviruses for use in oncolytic virus therapy. In addition, the use of NHP-derived adenoviruses in humans might be received warily given the recent zoonotic infections with influenza viruses and coronaviruses. In this review, we discuss the similarities and differences between human- and NHP-derived adenoviruses in view of their use as oncolytic agents. These include their genome organization, receptor use, replication and cell lysis, modulation of the host’s immune responses, as well as their pathogenicity in humans. Together, the data should facilitate a rational and data-supported decision on the suitability of NHP-derived adenoviruses for prospective use in oncolytic virus therapy.</jats:p>

Viral vector platforms within the gene therapy landscape

“… 119 Thus far, more than ten clinical trials using ChAd3-derived vaccine have demonstrated the safety of such replication-deficient vectors. 120 Moreover, high-capacity HCAd vectors can achieve long-term transgene expression in vivo, since they have dampened host immune responses against viral proteins that may be residually expressed. 121 To combat contamination by HV, self-inactivating HVs such as AdTetCre have been developed, in which a chimeric MerCreMer recombinase is regulated by a TetOn system to ensure effective elimination of HV.…”

Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

“…Another explanation for adenoviral binding to receptors located in intercellular junctions might be that we simply have not yet characterized all the receptors used by the different Ad types. This is true, especially, for the more recently developed non-human primate adenoviral vectors [ 15 ]. HAdV could bind to a more accessible entry receptor and use the cellular adhesion receptors for lateral spread.…”

“…Especially since some tumors downregulate CAR and most adenoviral vectors are still based on the CAR-binding HAdV-C5. Instead, research now aims to use other types of Ads, like non-human primate Ads [ 15 ] or genetically modified vectors that bind to an upregulated receptor on cancer cells [ 5 ]. However, regulations associated with genetically modified viruses complicate the approval for clinical use [ 108 ].…”

“…Besides less prevalent HAdVs, Ads from another host species, such as non-human primates, can be used to circumvent the pre-existing immunity to HAdVs [ 14 ]. Non-human primate Ads especially are considered because of their low pathogenicity in their natural host and their genome similarity to HAdVs [ 15 ]. In addition, human cells are permissive to many of the Ad types isolated from the great apes.…”

“…In addition, human cells are permissive to many of the Ad types isolated from the great apes. Non-human primate Ads do not circulate in the human population and therefore nAbs against these viruses are less prevalent, which is a major benefit of using non-human primate adenoviral vectors [ 15 ]. However, the receptors used for entry into the human cell by some low prevalent human and non-human primate Ads are not always known and might differ from HAdV-C5.…”