Oncolytic virotherapies represent a transformative approach to cancer treatment, harnessing the natural ability of viruses to replicate within tumour cells and trigger their destruction. Beyond direct lysis, these viruses stimulate powerful immune responses and can be engineered to express therapeutic transgenes within the tumour microenvironment, offering a multifaceted strategy to overcome tumour heterogeneity. Yet, despite this promise, clinical progress with oncolytic viruses has been limited, largely due to challenges in achieving sufficient tumour selectivity. 

To overcome this barrier, our laboratory has taken a structural biology-led approach to re-engineer adenovirus type 5 (Ad5), dissecting the molecular interactions that drive natural infection. From this, we created Ad5NULL—a fully detargeted, replication-competent virus rendered incapable of entering normal cells. This unique platform provides a safe and versatile foundation for precision re-targeting. 

We subsequently introduced the A20 peptide, a 20–amino acid ligand that binds with exceptional specificity to αvβ6 integrin, a molecule absent from healthy tissue but highly expressed in a broad range of aggressive epithelial cancers. The resulting vector, Ad5NULL-A20, selectively homes to and destroys αvβ6-positive tumours in vivo, exemplifying a new class of “precision virotherapies.” Moreover, this platform can be “armed” with potent immunostimulatory payloads—such as chemokines or bispecific immune activators—to further enhance anti-tumour efficacy. 

Our lead candidate, Ad5NULL-A20 expressing an immune checkpoint inhibitor (Trocept-01/ATTR-01), has entered first-in-human clinical evaluation. The ATTEST trial (ISRCTN38972074), an intravenous dose-escalation study across multiple UK cancer centres, marks a pivotal step towards realising the full therapeutic potential of this next-generation oncolytic platform.