Oncolytic Adenoviruses Armed with Co-Stimulatory Molecules for Cancer Treatment

Abstract

In clinical trials, adenovirus vectors (AdVs) are commonly used platforms for human gene delivery therapy. High genome capacity and flexibility in gene organization make HAdVs suitable for cloning. Recent advancements in molecular techniques have influenced the development of genetically engineered adenovirus vectors showing therapeutic potential. Increased molecular understanding of the benefits and limitations of HAdVs in preclinical research and clinical studies is a crucial point in the engineering of refined oncolytic vectors. This review presents HAdV species (A–G) used in oncotherapy. We describe the adenovirus genome organizations and modifications, the possibilities oncolytic viruses offer, and their current limitations. Ongoing and ended clinical trials based on oncolytic adenoviruses are presented. This review provides a broad overview of the current knowledge of oncolytic therapy. HAdV-based strategies targeting tumors by employing variable immune modifiers or delivering immune stimulatory factors are of great promise in the field of immune oncologyy This approach can change the face of the fight against cancer, supplying the medical tools to defeat tumors more selectively and safely.

Advances of Recombinant Adenoviral Vectors in Preclinical and Clinical Applications

“…The use of recombinant Ad as an oncolytic vector represents a novel strategy in cancer therapy, increasingly recognized in clinical trials since 2001, when oncolytic Ad (OAd) Onyx-015 was employed as a therapeutic intervention for advanced pancreatic cancer [ 204 , 205 ]. A critical requirement for ensuring the safety and efficacy of this therapeutic approach is the replication of OAd exclusively in tumor cells while healthy tissue does not perfectly enable vector replication [ 206 ]. The prototype of Ad-mediated virotherapy was ONYX-015 [ 207 ], an OAd characterized by a deletion in the region coding for E1b protein.…”

“…Despite the good affinity of oncolytic Ads of species D for CD46 and salicylic acid [ 213 ], their short fiber reduces the binding affinity to the Ad receptor, making them more suitable for vaccine development [ 214 ]. In addition, oncolytic Ads from groups E, F, and G, which primarily interact with CAR receptor, have not been successful in this therapeutic context [ 206 ].…”

“…Notably, armed Ad vectors carrying molecules such as GM-CSF [ 220 ], IL-12 [ 221 ], IL-15 [ 222 ], INF-γ [ 223 ], and TNF-α [ 224 ] have demonstrated significant success in clinical trials. A recent advancement involves the combination of armed OAd with chimeric antigen T-cell (CAR-T) therapy [ 225 ], as well as chimeric antigen receptor-NK cell therapy [ 206 , 226 , 227 ]. These applications show the potential for armed OAd to play a pivotal role in the future landscape of cancer treatment.…”

Clinical Advances and Future Directions of Oncolytic Virotherapy for Head and Neck Cancer

“…AD contains a double-stranded DNA ranging from 26 to 45 kb, and is currently the most frequently used virus vector in cancer biotherapy. It can cause symptoms of upper respiratory tract infections [56,57]. The primary receptor for AD is the Coxsackie-adenovirus receptor (CAR), with other receptors including CD46, CD80, CD86, and desmoglein-2 (DSG2) [58].…”

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors

“…Oncolytic virus (OV) therapy is a potentially useful treatment strategy especially in the wake of the success of checkpoint inhibitors to generate de novo or boost pre-existing native immune responses. Firstly, OVs selectively infect and lyse cancer cells, taking advantage of the tolerogenic mechanisms, which operate in tumors, and therefore act as an in-situ cancer vaccine via the release of tumor-associated and tumor-specific antigens and danger signals [ 1 ]. Secondly, they have the potential to beneficially remodel the tumor microenvironment from cold or non-inflamed to hot or T-cell inflamed for more effective anticancer immunity through a domino effect of cell lysis, transgene expression, antigen presentation, and adaptive immune activation [ 2 ].…”