Cancer: Developing 3D multicellular tumour spheroid models to assess EPA-oncolytic viruses combination therapies in vitro

Cancer immunotherapy holds significant promise for the treatment of a range of cancers. Immunotherapy efficacy, such therapeutic antibodies and oncolytic viruses (OVs), have been clinically assessed against a range of solid tumours. However, positive therapeutic responses are often limited as many immune evasion strategies exist within the tumour. For example, cyclooxygenase (COX2)-mediated production of prostaglandin E2 (PGE2) modulates a range of tumour promoting phenomena including migration and the induction of an immunosuppressive tumour microenvironment [1]. Therefore, intensive research efforts are being made to identify combination therapies that can potentiate the response to immunotherapies.

OVs are viruses that 1) replicate preferentially in cancer cells, causing cell death, and 2) induce innate and adaptive anti-tumour immunity [2]. OV have been investigated as anti-cancer agents for many years and their efficacy against a variety of different tumour types has been reported. Moreover, numerous OV clinical trials have demonstrated their safety and efficacy in cancer patients. Our preliminary work has identified eicosapentaenoic acid (EPA) as a promising agent to potentiate OVs. Pre-clinical and clinical evidence has demonstrated that EPA has anti-inflammatory and anti-cancer activity [3] and although EPA mechanisms of action are multifactorial, EPA-driven reduction of PGE2 production by COX-2 plays a key role in its anti-inflammatory properties and anti-cancer activity.

One significant difficulty in the pre-clinical assessment of anti-cancer immunotherapy combinations is that standard in vitro models do not replicate the complexity of the tumour microenvironment, whilst animal models are time consuming and expensive. Therefore, the aim of this project is to develop a range of multi-cellular tumour spheroids (MCTS) to better recapitulate the tumour microenvironment, investigate the interaction between cancer cells, fibroblasts and immune cells in 3D models, and test the anti-cancer activity of immunotherapy-based treatment combinations. Importantly, the development and optimization of these model systems will allow screening for efficacious combinations and identify potential biomarkers of response ahead of validation in vivo. The successful student will generate and optimize the growth of a range of 3D spheroid cultures, from spheroids made solely of cancer cells to spheroids encompassing multiple cell types including cancer cells, fibroblasts, monocytes, and PBMC. They will then characterise the immunosuppressive signals induced in these 3D models and determine the impact of different treatment combinations on immunosuppressive signalling. Importantly, This work will be performed in close relation with other researchers working on OV and EPA mechanisms of action.

This project will utilise sterile tissue culture techniques, for growth of cancer cell lines, fibroblasts and immune cells, flow cytometry for cell phenotyping and immunoassays, including ELISA. The student will use established cell culture techniques to grow MCTS and collect conditioned medium to assess soluble mediators and will characterise the cellular components of the established spheroid using immunohistochemistry methods. Ultimately this work aims to support the development of novel clinical strategies which will potentiate immunotherapy, starting with EPA and oncolytic viruses.

Eligibility:

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 of Medicine and Health minimum requirements are:

• British Council IELTS - score of 7.0 overall, with no element less than 6.5
• TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

How to apply:

Applications can be made at any time. To apply for this project applicants should complete an online application form and submit this 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.

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to [Email Address Removed]

Any queries regarding the application process should be directed to [Email Address Removed]