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Cancer: Investigating Modulators of Oncolytic Virotherapy for Treatment of Melanoma

PGR-P-462

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Fiona Errington-Mais and Dr Laura Matthews
Additional supervisors
Dr Elizabeth Ilett Dr Matt Bentham
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

Oncolytic viruses (OVs) preferentially infect and kill cancer cells, and their clinical efficacy has been demonstrated against a number of different cancers. The most clinically advanced OV is a genetically engineered herpes simplex virus (T-VEC) which expresses GMCSF to aid the development of anti-tumour immune responses; T-VEC is approved for the treatment of metastatic melanoma. OVs use multiple mechanisms to induce their anti-cancer effects including: (i) preferential viral replication in cancer cells and subsequent cell death - a process known as oncolysis; and (ii) stimulation of both innate and adaptive anti-tumour immune responses capable of eradicating malignant cells.? However, the tumour microenvironment comprises a complex network of cell-cell interactions, and multiple mechanisms exist which support tumour growth including: (i) the release of cancer promoting growth factors and cytokines; and (ii) the presence of regulatory immune cells (e.g. MDSC and Tregs) and immune checkpoints which act to inhibit cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell anti-cancer activity. Over recent years, a greater understanding of the tumour microenvironment has enabled researchers to design complementary combination therapies which enhance OV efficacy.

<h2 class="heading hide-accessible">Full description</h2>

<p>The anti-inflammatory glucocorticoid (Gc), cortisol, is released into the circulation with a daily rhythm and peaks at the onset of waking; cortisol is also released in response to stress. &nbsp;The complex effects of cortisol on cell fate and immunity make it difficult to predict how it might affect OV efficacy, both in terms of direct oncolysis or activation of host anti-viral, and anti-tumour, immune responses. &nbsp;Therefore, this PhD project will characterise the effect of endogenous cortisol on the efficacy of a range of OV using melanoma as a well characterised model system amenable to both direct oncolysis and OV induced anti-viral/anti-tumour immune responses. &nbsp;Specifically, this project will examine the effect of cortisol on: (i) direct OV killing of melanoma cell lines, (ii) OV driven inflammation; and (iii) OV-induced innate and adaptive immune activation. &nbsp;This work will be carried out using established in vitro human model systems and has the potential to progress to in vivo studies. &nbsp;</p> <p>This&nbsp;project will generate the first direct experimental evidence to&nbsp;determine whether the timing of OV&nbsp;administration&nbsp;affects&nbsp;their&nbsp;efficacy&nbsp;in melanoma,&nbsp;either as a direct lytic agent for immunotherapeutic tools. Importantly, this project also&nbsp;has the potential to&nbsp;inform&nbsp;the&nbsp;application&nbsp;of OV&nbsp;to&nbsp;other cancer types.</p> <p>In this PhD&nbsp;project&nbsp;students&nbsp;will&nbsp;learn a range of&nbsp;cellular&nbsp;and molecular biology techniques&nbsp;including&nbsp;2D and 3D&nbsp;cell culture&nbsp;models; viral&nbsp;propagation and&nbsp;infection;&nbsp;siRNA transfection;&nbsp;cell&nbsp;viability&nbsp;assays; ELISA;&nbsp;RT-PCR;&nbsp;ChIP-PCR;&nbsp;flow cytometry;&nbsp;immunoblotting&nbsp;and immunofluorescent microscopy.&nbsp;Importantly, there will also be an opportunity to gain&nbsp;in vivo&nbsp;experience,&nbsp;if desired by the appointed PhD student.&nbsp;&nbsp;These skills provide a solid basis to pursue a career in most biology fields but the appointed student will develop background knowledge and specific expertise that is particularly relevant to a career&nbsp;in cancer research,&nbsp;cancer biology and/or&nbsp;cancer&nbsp;immunology.&nbsp;</p> <p>References</p> <p paraeid="{279ac1ab-199a-4884-b9e6-22432358191f}{113}" paraid="1854840353">Gibbs J,&nbsp;Ince&nbsp;L, Matthews L, Mei J, Bell T, Yang N,&nbsp;Saer&nbsp;B, Begley N,&nbsp;Poolman&nbsp;T,&nbsp;Pariollaud&nbsp;M, Farrow S,&nbsp;DeMayo&nbsp;F,&nbsp;Hussell&nbsp;T, Worthen GS, Ray D, Loudon A. (2014)&nbsp;<a href="https://www.nature.com/articles/nm.3599">An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action</a>.&nbsp;Nature Medicine.&nbsp;20(8), pp. 919-926&nbsp;</p> <p paraeid="{279ac1ab-199a-4884-b9e6-22432358191f}{168}" paraid="1962825735">M&uuml;ller LME, Holmes M, Michael JL, Scott GB, West EJ, Scott KJ, Parrish C, Hall K, St&auml;ble S, Jennings VA, Cullen M, McConnell S, Langton C,&nbsp;Tidswell&nbsp;EL,&nbsp;Shafren&nbsp;D, Samson A, Harrington KJ,&nbsp;Pandha&nbsp;H, Ralph C, Kelly RJ, Cook G, Melcher AA,&nbsp;Errington-Mais&nbsp;F. (2019)&nbsp;<a href="https://www.ncbi.nlm.nih.gov/pubmed/31262361" rel="noreferrer" target="_blank">Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21.</a>&nbsp;J&nbsp;Immunother&nbsp;Cancer. Jul 1;7(1):164.&nbsp;&nbsp;</p> <p paraeid="{279ac1ab-199a-4884-b9e6-22432358191f}{168}" paraid="1962825735">Berkeley RA, Steele LP, Mulder AA, van den&nbsp;Wollenberg&nbsp;DJM,&nbsp;Kottke&nbsp;TJ, Thompson J, Coffey M,&nbsp;Hoeben&nbsp;RC, Vile RG, Melcher A,&nbsp;Ilett&nbsp;EJ.&nbsp;(2018)&nbsp;<a href="https://www.ncbi.nlm.nih.gov/pubmed/30209061" rel="noreferrer" target="_blank">Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy.</a>&nbsp;Cancer Immunol Res. Oct;6(10):1161-1173.&nbsp;&nbsp;</p> <p>This project is part of the&nbsp;<a href="https://medicinehealth.leeds.ac.uk/leeds-institute-research-st-james/doc/international-phd-academy-medical-research">International PhD Academy: Medical Research</a></p> <p><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete an <a href="http://www.leeds.ac.uk/info/130206/applying/91/applying_for_research_degrees">online application form</a> and submit this&nbsp;alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates. Please make it clear in the research information section that you are applying for the International PhD Academy: Medical Research, as well as the title of the project you wish to be considered for.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &bull; British Council IELTS - score of 6.5 overall, with no element less than 6.0 &bull; TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

<h2 class="heading">Contact details</h2>

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting LIMRPhD@leeds.ac.uk.</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School&nbsp;Office&nbsp;e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked funding opportunities</h3>
<h3 class="heading heading--sm">Linked research areas</h3>