Combination oncolytic virotherapy for the treatment of Haematological malignancies

Project description

Oncolytic viruses (OV) are viruses that 1) replicate preferentially in cancer cells, causing cell death, and 2) induce anti-tumour immunity, through activation of both innate and adaptive immune responses.  OV has been investigated as anti-cancer agents for many years and their efficacy against a variety of different tumour models has been reported. Numerous OV clinical trials have provided a body of evidence demonstrating their safety and efficacy in cancer patients, particularly for solid malignancies.  Disappointingly, the efficacy of OV against haematological malignancies (HM) is comparatively under-investigated and significant pre-clinical research is required in this area to facilitate the clinical translation of OV for the treatment of HM.

The presence of multiple sub-clones in HM makes a durable cure with a single therapeutic agent unlikely due to the accumulation of drug-resistant cells and subsequent relapse of the patient. Therefore, there is a need to develop combination strategies to eradicate diverse disease phenotypes and drug-resistant cells. Our work has shown that the efficacy of OV against HM can be increased using combination approaches to either, 1) boost direct cytotoxicity, or 2) potentiate anti-tumour immune responses.  Examples include; the ability of OV to activate innate immune effector cells, Natural Killer (NK) cells, and potentiate CD20-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia (CLL; Parrish et al., 2015); and enhanced killing of drug-resistant CLL cells using reovirus in combination with either standard of care chemotherapy agents, such as fludarabine, or novel agents which are currently showing promise in clinical trials, e.g. BH3 mimetics.

This project aims to 1) test novel combination strategies to potentiate the efficacy of OV against HM, and 2) evaluate the molecular mechanisms responsible for the additive or synergistic responses observed.   This project will develop skills in i) sterile tissue culture techniques, for the growth of cancer cell lines and, where possible, primary patient samples, ii) multi-colour flow cytometry for cell phenotyping and viability assays and iii) immunoassays including ELISA.  Additional techniques that may be used include MTT/MTS metabolic assays, PCR, and/or western blot.  Ethical approval is already in place for access to primary samples.  

References:

Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia. Parrish C, Scott GB, Migneco G, Scott KJ, Steele LP, Ilett E, West EJ, Hall K, Selby PJ, Buchanan D, Varghese A, Cragg MS, Coffey M, Hillmen P, Melcher AA, Errington-Mais F. Leukemia 2015 Sep;29(9):1799-810. PMID: 25814029

Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites.  Jennings VA, Ilett EJ, Scott KJ, West EJ, Vile R, Pandha H, Harrington K, Young A, Hall GD, Coffey M, Selby P, Errington-Mais F, Melcher AA. Int J Cancer. 2014 Mar 1;134(5):1091-101.

Entry requirements

This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidates 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 minimum requirements are

• British Council IELTS - score of 6.5 overall, with no element less than 6.
• 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.

Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

How to apply

Applications can be made at any time. Potential applicants are welcome to contact Dr Fiona Errington-Mais with informal enquiries about this research project.

To formally apply for this project applicants should complete a Faculty Scholarship Application form and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly by email 

If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.