Theme 3 – Combining radiotherapy with novel therapies

Theme 3 aims to accelerate and deliver new radiotherapy combination treatments to the clinic, focusing on our tumour sites of interest in pelvic, brain and liver cancers.

Theme Leads

Dr Adel Samson (Co-Lead)

Associate Professor, Medical Oncologist

Staff Profile: Dr Adel Samson | School of Medicine | University of Leeds

Professor Susan Short (Co-Lead)

Professor of Clinical Oncology, brain tumours

Staff Profile: Professor Susan Short | School of Medicine | University of Leeds

Work Package 5 – Translational research in clinical trial cohorts

Work package 5 focuses on high quality translational research that will link discovery science to the clinic. This will be achieved through efficient use of tissue and development and exploitation of novel models in the lab. WP5 includes three seed funded projects:

Radio-Immunotherapy for Glioblastoma Multiforme – Translational Analyses in the ReoGlio Trial (PI: Dr Adel Samson)
  • Patients with newly diagnosed glioblastoma have a median overall survival of just 15 months with current radiotherapy-Temozolomide protocols. Whilst immunotherapy using immune checkpoint blockade (ICB) has revolutionised the management of numerous solid malignancies, not all cancer types are sensitive, largely due to a lack of pre-existing tumour-infiltrating lymphocytes and inadequate tumour antigen presentation. Specifically, in glioblastoma, two phase 3 clinical trials testing ICB in combination with radiotherapy in newly diagnosed glioblastoma, failed to achieve the primary outcome of improved overall survival in comparison to standard care.
  • In Leeds, we have recently completed the ReoGlio trial, where an intravenous oncolytic virus (OV) was combined with standard of care radiotherapy and temozolomide in newly diagnosed glioblastoma, with the aim of enhancing immunogenic cell death. This project will utilise serial translational blood samples from patients within the ReoGlio trial to discern evidence for OV immune priming to sensitise glioblastoma to ICB. We will identify the most promising ICB drugs and schedules for combination with OV-radiotherapy and build preliminary data for funding applications to support a trial of an OV plus ICB alongside standard temozolomide-radiotherapy in patients with newly diagnosed glioblastoma.
Translational Analyses in Patients Receiving Stereotactic Ablative Radiotherapy for Hepatocellular Carcinoma (PI: Dr Adel Samson)
  • The use of Stereotactic Ablative Radiotherapy (SABR) in the treatment of hepatocellular carcinoma (HCC) was recently commissioned by NHS England. Despite excellent and durable local control rates, median overall survival for patients with HCC following SABR is limited to around 18 months. This is predominantly due to the appearance of metastatic disease or new primary HCC lesions within the liver. Strategies to enhance the systemic immune-mediated anti-HCC effects of SABR, may therefore limit the emergence of HCC lesions in non-irradiated sites and improve survival. 
  • This project will identify the principal radiotherapy immune resistance mechanisms in HCC, during and after SABR, by way of a translational study of serial peripheral blood samples. These immune-resistance mechanisms will subsequently be targeted, in a pre-clinical T-cell anti-cancer model of HCC, to identify candidate combination immunotherapy drugs to enhance the systemic efficacy of SABR in HCC and rationally inform future SABR-immunotherapy clinical trials in HCC.
Patient Derived Glioma Assembloids (PIs: Mr Ryan Matthew and Dr Heiko Wurdak)

Glioma is a brain cancer of unmet need. Currently, patient outcomes are very poor and even aggressive treatment strategies cannot provide a cure. Neurosurgery and adjuvant chemoradiotherapy eliminate most of the tumour mass but highly adaptive residual cells with stem cell-like capability resist therapy and cause inevitable tumour recurrence. A better understanding of the radioresistant glioma cell population is urgently required. To this end, we have established a novel experimental paradigm that is based on the real time observation of glioma cell infiltration into human induced pluripotent stem cell (iPSC)-derived organoids. These so-called ‘assembloids’ enable the testing of diverse treatment modalities in the laboratory (in parallel) to study the effects of these modalities on the radioresistant and tumour-repopulating cell compartment at the tumour and brain tissue interface. Here, we aim to elucidate the genes and molecular networks that critically help the glioma cells to adapt to the pressures of radiation-induced stress in their complex 3-dimensional environments. Ultimately, we hope that the results reveal additional therapeutic targets and agents with the potential to increase the benefit of radiotherapy in glioma patients.

Other WP5 Researchers

Professor David Sebag-Montefiore
Mr Ryan K Mathew

Associate Professor (Clinical)

Staff Profile: Mr Ryan K Mathew I School of Medicine I University of Leeds

Dr Heiko Wurdak

Lecturer/Group Leader

Staff Profile: Dr Heiko Wurdak I School of Medicine I University of Leeds

Work Package 6 – Combining radiotherapy with novel therapies

Work package 6 exploits our expertise in clinical study design and execution to bring new combination approaches to the clinic. This will include new relationships with industry partners as well as increased partnership with medical oncology colleagues.

Other WP6 Researchers

Professor David Sebag-Montefiore