PhD in Cancer Virotherapies - Development of precision virotherapies capable of evading anti-vector immunity.

The use of “oncolytic” viruses has immense potential in the cancer setting where the therapeutic self-amplifies, through replication, at the site of need (i.e. within the tumour microenvironment). Whilst the immune-stimulatory effects of tumour cell lysis induced by virotherapies alone has therapeutic potential in the cancer setting, efficacy can be augmented significantly through the incorporation of DNA encoding additional therapeutic modalities within the viral genome, for targeted, tumour specific overexpression.

The Parker lab have made great strides in developing bespoke adenoviral (Ad) based virotherapies that are capable of tumour selective cellular infection. To achieve this, we generated a viral backbone ablated for all known native means of cellular uptake via genetic modification of all three major capsid proteins, hexon, fiber and penton base. The resultant vector, Ad5NULL cannot be produced in vitro as it is so defective in cellular uptake and can only be “rescued” through the incorporation of peptides to target the recombinant virus to alternative cellular receptors. We achieved this through the incorporation of a 20 amino acid peptide (A20) into the Ad fiber protein which binds αvβ6 integrin with high affinity. The epithelial specific αvβ6 integrin is not expressed in healthy epithelia but is commonly expressed in aggressively transformed tumour types. The resultant vector, Ad5NULL-A20 is only able to infect αvβ6 positive cells in vitro and in vivo, providing a highly tumour selective virotherapy platform for delivery of therapeutics in vivo.

A limitation that may thwart the full potential of this technology is the prevalence of pre-existing anti-vector immunity in the general population. In the UK, it is thought to that 30-50% of the population present pre-existing anti-Ad5 immunity, which may limit the efficacy of virotherapies based on Ad5 in the seropositive proportion of the population. Even in the proportion of the patient population who are seronegative, the ability to re-administer the therapeutic following initial dosing will be limited by seroconversion of the patient from a seronegative to seropositive status following administration of the therapeutic. Therefore, development of “neutralisation resistant” vectors based on Ad5NULL-A20 could have important implications for (a) the successful treatment of patients who present with αvβ6+ tumour types who are Ad5 seropositive, and (b) for the re-administration of Ad5NULL-A20 based therapies in patients with relapsed αvβ6+ disease.

In this project, we will focus on the Ad5 hexon protein, which has previously been demonstrated to be the immunodominant epitope in Ad5. In this project, we will therefore develop new versions of our bespoke precision virotherapy, Ad5NULL-A20, that can circumvent anti-Ad5 immunity. To achieve this, we will develop hexon chimeric Ad5 based virotherapies, where HVRs from low seroprevalance serotypes are pseudotyped into Ad5NULL-A20. As an alternative approach, novel rarely isolated (and thus low seroprevalance) Ad serotypes will evaluated for their potential to target and infect using A20/αvβ6 mediated pathways, and their ability to bypass anti-Ad5 immunity will be assessed.

The project is fully and generously funded for 4 years by Cancer Research UK, as part of a wider Programme grant developing “precision immunovirotherapies” for clinical translation.

The successful student will join a thriving, expanding and talented team, with wide connections to groupings and expertise in virology and immunology.