EPSRC Centre for Doctoral Training in Engineered Tissues for Discovery, Industry and Medicine

Immune checkpoint blockers (ICBs) which regulates immune response against cancer have revolutionized cancer therapy, but the efficacy of ICBs is low when tumours metastasise to the liver1. This is a huge challenge since the liver is one of the commonest sites for secondary tumours. Furthermore, only 20% of primary liver cancer patients are responsive to immunotherapy2. The liver microenvironment therefore appears to be a major driver in suppressing tumour specific responses making cancer therapy less efficient.
The liver is a tolerogenic organ with liver sinusoidal endothelial cells (LSEC), which line the fine blood vessels in the liver, making a critical contribution to the tolerogenic microenvironment3. LSEC can alter immune cell function and act as the gatekeeper to immune cell infiltration into the liver, controlling which immune cell subsets are recruited from the circulation4. The importance of LSEC is often overlooked during tissue regeneration and cancer, and we have pilot data showing that human liver endothelium is reprogrammed by the tumour microenvironment and likely to form a barrier to effector T cell recruitment/activation. The investigation of human liver tumour microenvironment is challenging as animal models do not fully recapitulate the cause and mechanisms of human disease. For example, the differences in immune components and response against disease. To overcome this limitation, we aim to harbour the leading technologies used in regenerative medicine by developing a three-dimensional human liver tumour model to investigate the crosstalk between the tumour epithelium, endothelial cells, and the immune cells.

Aim 1 To develop a culture system with cellular components derived from the same patients to recapitulate tumour microenvironment in vivo. Alternative co-culture system such as the Transwell and the Ibidi trafficking chambers are also in place.

Aim 2 To investigate the effect of tumour microenvironment on T-cell trafficking. T-cells will be isolated from blood samples obtained from patients and culture with the organoids. T-cell trafficking and phenotype will be investigated after culturing with organoids derived from patients or non-tumourous donor.

Aim 3 We will test whether inhibiting the endothelial factors identified in previous aims leads to a synergistic effect with immune checkpoint inhibitors on T cell infiltration in this 3D tumour/endothelial model.
The student will learn a range of techniques with hands on experience from tissue collection, cell isolation and model generation. These include, histological analysis, cell isolation by FACS, cell/organoid culture, molecular and transcriptional analysis.

The training opportunities will support novel approaches to cancer therapy by using state of the art interdisciplinary techniques in an in vitro setting to 1) develop a patient-derived novel 3D liver model 2) Identify molecular pathways by which tumours affect endothelial cell/ T cell crosstalk.

The student will have close link to the NHS and National Institute for Health Research through the supervisor Dr Shetty. Dr Shetty is a consultant hepatologist who specialized in liver cancer at the Queen Elizabeth Hospital, Birmingham. The involvement of Dr Shetty in this project aims to tackle what is currently lacking in clinics, with only 20% of liver cancer patients responds to immune checkpoint blockade treatment. This will generate outputs which is clinically relevant and translatable which can have a positive impact on human health in the future. In terms of student development, the student will have a wealth of experience in basic and translational research, incorporating the fundamentals of biomedical sciences with chemical engineering. The student will benefit from the breadth and multidisciplinary of research areas, and motivated by the goals of this project which directs to improve patient health.

Humanised, 3D tissue models are finding interest due to current overly-simplified immortal cell lines and non-human in vivo models providing poor prediction of drug safety, dosing and efficacy; 43% of drug fails are not predicted by traditional screening and move into phase I clinical trials1. Phase I sees a 48% success rate, phase II a 29% success rate and phase III a 67% success rate [1]. The drug development pipeline is pressurised due to adoption of high throughput screening / combinatorial libraries. However, while R&D spend has increased to meet this growing screening programme, success, measured by launched drugs, remains static [2]. This poor predictive power of the >1 million animals used in the UK each year drives the 12-15 year, £1.85B pipeline, for each new drug launch [3]. Contract research organisations (CROs) are also similarly hit by these problems.

Drive to reduce animal experimentation in toxicology and outright banning of animal testing for e.g. cosmetics in the UK has driven companies to outsource or to adopt the limited number of regulator approved NAT models for e.g. skin [4,5].

Another key area that uses 3D tissues is the field of advanced therapeutic medicinal products (ATMPs), i.e. tissue engineering/regenerative medicine. Regulation is a major ATMP bottleneck. It is thus noteworthy that regulators, such as the UKs Medicines and Healthcare Products Regulatory Agency (MHRA), are receptive to the inclusion of NAT-based data in investigative medicinal product dossiers [6].

The lifETIME CDT will directly address these issues through nurturing of a cohort training not only in the research skills required to conceive and design new NATs, but also in skills based on:

- GMP and manufacture.
- Commercialisation and entrepreneurship.
- Regulation.
- Drug discovery and toxicology - a focus on the end product.
- Policy.
- Public engagement.

Our NAT graduate community will impact on:

- Pharma - access to skills that develop tools to unlock their drug discovery and testing portfolios. By helping train graduates who can create and deploy NATs, they will increase efficiency of drug development pipelines.

- ATMP manufacturers - the same skills and tools used to deliver NAT innovation will help to deliver tissue engineered / combination product ATMPs.

- CROs - access to skills to create platform tools providing more sophisticated approaches to the diverse research challenges they face.

- Catapult Centres - access to skills that provide innovation that can be deployed across the broader healthcare sector.

- Regulatory agencies e.g. MHRA - better education for the next generation of scientists on development of investigational new drug / medicinal product dossiers to speedup approvals.

- Clinicians and NHS - access to more medicines more quickly through provision of highly skilled scientists, manufacturers and regulators. NATs will help drive the stratified/personalised medicine revolution and understand safety and efficacy parameters in human-relevant tissues. Clinicians will also benefit from development of ATMP-based regenerative medicine.

- Patients - benefit from skills for faster and more economically streamlined development of new medicines that will improve lifespan and healthspan.

- Public and Society - benefit from the economic growth of a thriving drug development industry. Benefits will be direct, via jobs creation and access to wider and more targeted healthcare products; and indirect, via increased economic benefit of patients returning to work and increased tax revenues, that in turn feed back into the healthcare systems.


[1]. Cook. Nat Rev Drug Discov 13, 419-431 (2014).
[2]. Pammolli. Nat Rev Drug Discov 10, 428-438 (2011).
[3]. DiMasi. Health Econ 47, 20-33 (2016).
[4]. Cotovio. Altern Lab Anim 33, 329-349 (2005).
[5]. Kandarova. Altern Lab Anim 33, 351-367 (2005).
[6]. https://goo.gl/i6xbmL