Initially developed as cytotoxic agents, the anti-tumour properties of oncolytic viruses (OV) are now known to be largely immune-mediated. However, as well as inducing anti-tumour immune responses, OV also stimulate anti-viral responses, including the production of OV-specific neutralizing antibodies (NAb). Antibody-neutralization of viruses is thought to be irreversible, hence the current perception that the presence of either pre-existing anti-viral NAb in patients, or their development during viral therapy, are a barrier to systemic OV delivery, because they will prevent the virus accessing the tumour. This means that repeat systemic OV dosing would be ineffective. Systemic delivery is the preferred clinical option, being both broadly applicable and suitable for targeting visceral or widespread metastatic disease. Thus, if NAb are a complete therapeutic barrier, OV delivery will be limited to either direct intra-tumoural injection, which is technically challenging and only suitable for readily accessible tumours, or alternatively to a restricted ‘one shot cure’ approach. However, clinical trials have shown that oncolytic reovirus can access tumours in patients, despite the presence of NAb. We have also shown that human monocytes loaded with pre-formed reovirus-NAb complexes (reoNAb), in which the reovirus is fully neutralized, can deliver functional replicative reovirus to tumour cells resulting in tumour cell infection and lysis. We have also found that monocytes loaded with reoNAb stimulate natural killer cell-mediated cytotoxicity, but a detailed analysis of the effects of OV-NAb on the induction of innate and adaptive anti-tumour immune responses is lacking. There are several OV currently under clinical development but if they are to be used to their full potential in patients, a detailed understanding of the effect that pre-existing anti-viral NAb have on the induction of anti-tumour immune responses is required.
This project will compare the effect of OV-NAb vs non-neutralized OV on the activation phenotype and function of different immune cell subsets in the blood.
The successful student will generate OV-NAb complexes using OV and serum collected from patients treated with OV. The effect of OV-NAb on the activation phenotype of immune cell subsets will be compared with that of non-neutralized OV using FACS analysis of surface marker expression. The cytokine profiles of OV-NAb-treated vs OV-treated immune cells will be examined by ELISA or Luminex® multiplex assay. Functional assays including 51Cr-release cytotoxicity assay, mixed lymphocyte reactions and our established CTL priming assay will also be used to assess innate and adaptive anti-tumour immune responses. There may also be the opportunity to be trained in animal work.
Supervisors: Dr Elizabeth Ilett; Dr Fiona Errington-Mais https://medicinehealth.leeds.ac.uk/medicine/staff/464/dr-elizabeth-ilett https://medicinehealth.leeds.ac.uk/medicine/staff/310/dr-fiona-errington-mais
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
Berkeley, Steele, Mulder, van den Wollenberg, Kottke, Thompson, Coffey, Hoeben, Vile, Melcher, Ilett. Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy. Cancer Immunol Res 2018; 6(10):1161-1173
Ilett, Kottke, Donnelly, Thompson, Willmon, Diaz, Zaidi, Coffey, Selby, Harrington, Pandha, Melcher, Vile. Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. Mol Ther 2014; 22(10):1851-63
Ilett, Bárcena, Errington-Mais, Griffin, Harrington, Pandha, Coffey, Selby, Limpens, Mommaas, Hoeben, Vile, Melcher. Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization. Clin Can Res 2011; 17(9):2767-2776