Title: Patient-specific 'tumouroids' to optimise response to cancer treatments
Funder: Department of Health and Social Care

Abstract: Our proposal is a direct response to the challenges described above. We seek to engineer tumouroids; 3-dimensional, biomimetic synthetic tumour models containing explanted human cancer tissue so that the cancer can be propagated and then subjected to treatment. We also intend to develop non-invasive monitoring systems that are responsive to cancer colony viability and cell count that can be applied at scale. Our proposal seeks to evaluate both the health and health economic benefit of therapeutic allocation on the basis of demonstrable response in parallel to existing trials. Our proposal is explicitly geared to producing a technology that will influence patient care, by means of its criterion and face validity, its wide availability and reasonable cost. We do however recognise that if this primary goal is not realised that other applications may be both possible and desirable. These include an important role in drug development, furthering our understanding of tumour biology and as a predictive tool that may provide synergies with genomic and epigenetic predictive models of the future. The project plan comprises the following work-streams (WS): WS 1.0 Engineer reproducible, quality controlled, 3-dimensional synthetic constructs that are biomimetic for lung, kidney, colon, and prostate. This work stream is about version and quality control of the tumouroid constructs. We believe our tumouroid to be unique in the extent to which it can be engineered and therefore specified and manufactured. It is a two-compartment model comprising a synthetic cancer mass embedded within a synthetic stroma. Once a reliable platform for each tumour type has been produced it will transition into the next work-stream WS 2.0 Generate cultures from explanted cancer cells derived from biopsy or surgical specimens to create tumouroids of non-small cell lung cancer; renal cancer; colon cancer; and prostate cancer. Validate the responsiveness of the model. This work-stream addresses the refinement and validation of the tumouroids that incorporate human explanted cancer colonies. Key attributes of validity comprise genetic homology relating to original cancer, morphological criteria and responsiveness of tumouroid to challenge (radiotherapeutic and chemotherapeutic). WS 3.0 Bioengineer immune-competence within the tumouroids. Deriving an immunocompetent model of cancer remains a key challenge. This work-stream seeks to establish whether levels of immune competence can be conferred onto tumouroids by inoculating the patient's own tumour infiltrating lymphocytes into the tumouroid. WS 4.0 Engineer tumouroid-monitoring systems for non-invasive assessment of cancer cell viability and dynamics. Another key attribute in relation to making tumouroid-directed care a possibility is the opportunity for accessible, inexpensive non-invasive assessment of colony viability. This work-stream compares a number of approaches. Those that fail to meet the target will be discarded in favour of those that do. WS 5.0 Assess concordance between the treatment-response observed in the patient-derived tumouroids vs that observed in the patient being treated within an established clinical trial. This represents our first phase of clinical evaluation and takes the form of a non-intervention study in which we compare the tumouroid-predicted response to therapy to that observed within a clinical trial setting. WS 6.0 Establish a stakeholder/public engagement programme that has a central role in the conduct of the project. This work-stream was the first to initiate and will run alongside the project. WS 7.0 Develop sustainable academic/commercial partnerships to assist in the exploitation and wider dissemination of the tumouroid technology. Our development programme so far has been integrated with three UK SMEs: TAP Biosystems; Oxford Opronix and Lein Applied Diagnostics. We have licensed IP to TAP and forsee opportunities for shared IP with all three, going forward. WS 8.0 Anticipate the health policy and health economic implications of incorporating tumouroids into clinical practice.

Lay abstract: Our vision is to create a new and better way to predict which cancer treatments will benefit individual patients. Many patients with cancer do not benefit from their treatment. Without benefit the consequences are harm; delay to definitive therapy and cost. Personalised medicine tries to predict which patient will benefit and which will not, and has become one of the fastest growing areas of cancer research. These predictions are usually made by analysing the genes within the tumour. However, making these predictions has proved very challenging because of the complexity of cancer cells which can adapt very quickly. An alternative is to test the patient s own cancer cells against a number of treatments and use the response to guide therapy. This is similar to the way we treat bacterial infections. To decide which antibiotic to give patients we grow the bacteria in a 'test tube' with a range of antibiotics. The antibiotic prescribed will be the one that has been demonstrated to work. If more than one works then the choice will be the cheapest or the one that is best tolerated by the patient. This approach has been tried with some success by growing patients cancer cells in small animals, but is time consuming, expensive and poses ethical dilemmas for some. Our proposal seeks to create an artificial model, called a tumouroid, where we grow patients own cancer cells in a &ldquo;test tube&rdquo; in the laboratory. These tumouroids will be monitored and treated with drugs and radiotherapy. If the tumouroids prove to be predictive of patients responses to treatment we would be in a position at the end of our study to conduct, subject to ethics approval and further funding, a clinical trial of tumouroid-directed therapy versus standard care.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS