Outline

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.

Within the Parker lab, we 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 to this technology is that whilst αvβ6 integrin represents an exciting, tumour selective antigen for many targeted virotherapy applications, not all tumour types express αvβ6 integrin. For example, whilst Pancreatic, Oesophageal, Gastric and Head and Neck Cancers are known to commonly and strongly express αvβ6 integrin, tumours of hepatic and prostate origin are known to be poor expressors of αvβ6 integrin. Therefore, the development of methodologies that enable targeting of virotherapies to alternative tumour associated antigens would be highly desirable, particularly in the context of the Ad5NULL background where native means of cellular uptake have been ablated.

Traditional methodologies, based on iterative selection of peptides from filamentous phage based libraries have largely failed translate their binding capacity from the phage-based context (where the peptide is presented as a linear entity) to the virus based context (where the peptide is presented as a constrained entity as part of the viral fiber knob domain). Indeed, our own research has highlighted the difficulties of this approach with peptides identified to bind the putative tumour antigens FGFR1, EGFR and Folate receptor α failing to recapitulate their targeting activity when presented within the three dimensional context of the adenoviral fiber knob protein, despite their presentation being seemingly compatible with receptor engagement.

In this project, the recruited PhD student will build upon radical alternative technologies for targeting adenoviral based vectors to tumour associated antigens. The recruited student will build both “rational” and “irrational” approaches to vector engineering. For “irrational” engineering, the student will generate novel Phage: Adenovirus libraries and assess binding to the target antigens in vitro and in silico, using the most promising variants to generate targeted virotherapies. For rational approached, the student will use existing known structural insights into receptor: ligand interactions and recapitulate these interactions within the context of the fiber knob protein. A final approach will be a non-genetic approach, through the development of biotinylatable Ad based vectors.

What is funded

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.

Eligibility

Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

How to Apply

This studentship has a start date of October 2020. In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)

There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2020). In the research proposal section of your application, please specify the project title and supervisors of this project and copy the project description in the text box provided. In the funding section, please select 'I will be applying for a scholarship/grant' and specify that you are applying for advertised funding from PhD in Cancer Virotherapies. This will take you to the application portal.

In order to be considered candidates must submit the following information:

• Supporting statement

• CV

• Qualification certificates

• References x 2 (optional but may strengthen your application)

• Proof of English language (if applicable)