Immune-activating radiotherapy plus CAR-T therapy for hepatocellular carcinoma induces epitope spreading

Main Applicant: Claire Roddie (UCL)
Co-Applicant(s): Erik Sahai (Crick), Maria Hawkins (UCL),  Harriet Roddy (UCL)

Unresectable Hepatocellular Carcinoma (HCC) is incurable with a dismal 2-11% 5y survival. Whilst Glypican-3 (GPC3) is an attractive Chimeric Antigen Receptor (CAR) T-cell therapy target, the effectiveness of GPC3-targeting CARs is limited by the immunosuppressive HCC tumour environment. We have shown that low-dose ‘immune-activating’ radiotherapy (RT) to HCC disease sites can improve tumour clearance. Here we will test if low-dose RT can also induce abscopal effects & epitope spread outside the RT field for even greater anti-HCC impact.

Identification of radiotherapy-induced changes in the tumour microenvironment of rectal cancers that may prime response to immunotherapy.

Main Applicant: Francesca Ciccarelli (Crick/QMUL)
Co-Applicant(s): Maria Hawkins (UCL), Manuel Rodriguez-Justo (UCL)

We will investigate how radiotherapy modifies the tumour immune microenvironment of rectal cancers to improve response to immunotherapy. Following up on recent results of our lab, we will focus on radiotherapy-induced variation of (1) CD74 protein levels in the tumour stroma and (2) intra-epithelial immune infiltration, as both are relevant for immunotherapy response. Our results will be compared with an ongoing clinical trial testing combination of radio and
immunotherapy, with the ultimate goal to improve stratification of patients who will benefit from radioimmunotherapy

Modelling radiation-resistance in high-grade gliomas

Main Applicant: Grace Cooksley, (UCL)
Co-Applicant(s): Silvia Marino (QMUL), Jamie Dean (UCL), Paula Alexandre (UCL), JP Martinez-Barbera (UCL)

Radiotherapy resistance is the leading cause of mortality in high grade glioma patients. Biopsies of patients post-treatment are rare, hindering our understanding of treatment response and tumour relapse. We propose using our cancer-organoid and microglia co-culture system, to model radiotherapy resistance and to monitor cell behavior and biology such as microglia’ cellular senescence, potentially contributing to poor treatment response and tumour regrowth

Using differentiation to target radio-resistance in childhood tumours of the brainstem

Main Applicant: Lucy Brooks (UCL)
Co-applicant(s): Chris Jones, Dr Manav Pathania

DIPGs are incurable childhood brainstem tumours which, despite radiotherapy, have a median survival <1 year. Tumours contain a population of stem/progenitor-like cells that retain the ability to partially differentiate toward oligodendrocyte-like (OL-like) or astrocyte-like (AC-like) cells. As stem-like cells are associated with therapy resistance, promoting differentiation may present a way to tackle resistance. This work aims to provide the necessary preliminary data to support fellowship applications to explore the relationship between cell fate and radiosensitivity.

Determining the role of adult liver progenitors in liver tissue tolerance to radiation

Main Applicant: Luigi Aloia (UCL)
Co-applicant(s): Stephen Turnock, Dr Maria Hawkins

Liver cancer is projected to have an increased incidence of 35% and become the second leading cause of cancer related death by 2035. Radiation has a limited use for liver cancer due to the low tissue tolerance and high tumour resistance. This proposal will test the hypothesis that promoting the activation of adult liver progenitors can considerably increase the tolerance of the liver tissue to radiation. This has important implications for the design of novel therapeutic strategies to widely implement radiotherapy for the treatment of human primary liver cancer.

Targeted molecular radiotherapy of αvβ6 expressing head and neck cancer

Main Applicant: Jane Sosabowski (QMUL)
Co-applicant(s): John Marshall (QMUL), Antony Kong (KCL), Phil Blower (KCL),  Jennifer Young (QMUL)

The epithelial-specific αvβ6 integrin is not expressed in normal oral epithelia, but is upregulated in carcinogenesis. We have demonstrated in vivo tumour targeting using αvβ6-specific peptide A20-FMDV2 radiolabeled with 68Ga and 111In, and that conjugation of A20-FMDV2 to a potent toxin shows efficacy in tumour models of pancreatic cancer. In this work, we propose conjugation of a chelator (DOTAM) suitable for radiolabeling with 203Pb for imaging and 212Pb for alpha particle therapy, to test the feasibility of molecular radiotherapy of head and neck squamous cell carcinoma (SSCHN) with a novel, highly cytotoxic radionuclide

Development of novel theragnostic radiopharmaceuticals for the imaging and treatment of the poor prognosis childhood cancer neuroblastoma.

Main Applicant: Mark Gaze (UCLH)
Co-Applicant(s): Samantha Terry (KCL) and Jane Sosabowski (QMUL)

We will radiolabel and evaluate paired antibody conjugates for imaging and molecular radiotherapy of neuroblastoma. The monoclonal antibody dinutuximab beta is a NICE-approved treatment for neuroblastoma. We will radiolabel with ⁸⁹Zr for PET imaging and with ¹⁷⁷Lu for therapy, using DFO and DOTA chelators. We will determine their cell targeting and radiobiological characteristics in cell culture models, and PET imaging in mice. This pilot work will enable grant applications for more detailed in vitro and preclinical studies and ultimately immuno-radiotherapy clinical trials.

Clinical outcomes for children and adults with primary brain tumours remain poor. Radiotherapy (RT) is delivered as one-size-fits-all, not taking into account biological heterogeneity. Multiparametric MRI provides information on tumour and normal brain and can inform adaptation based on early biological changes during RT. Techniques including proton beam therapy (PBT) can reduce radiation dose to normal brain cognitive networks whilst increasing RT to tumour regions. This work will guide the design of a future clinical trial of adaptive RT for glioma.

Proteomic analysis of Polθ interactome in clinically relevant conditions such as g-irradiated and hypoxia exposed cells and characterization of the response to Polθ inhibitors. Functional characterization of Polθ interacting proteins and their role in genome stability. In silico analysis of DDR gene expression in hypoxia using available RNAseq data from hypoxia-exposed cancer cell lines.

Boosting anti-tumour immunity through Radiotherapy induced re-education of adoptively transferred monocytes

Radiotherapy (RT) is known to promote monocytes (MO) trafficking and differentiation into different subsetsat the irradiation site. We proposed to combine RT and the adoptive transfer of MO engineered to deliver inflammatory mediators in order to remodel the immune tumour microenvironment. We will characterise the impact of RT on MO differentiation within tumours as well as the potential role of MO-derived IL-12 as a tool for further reprograming of the immune tumour microenvironment towards an anti-tumour microenvironment.

We will study the molecular processes seen in tumours of patients who have completed pre-operative radiotherapy for soft tissue sarcoma (STS) in the CRUK-funded IMRiS clinical trial. This hypothesis-generating study will investigate the role of (i) telomere biology in radiosensitivity, (ii) mutational signatures including DNA repair pathways, (iii) machine learning models to develop molecular predictive biomarkers, with the aim of producing data for future validation studies and a prospective clinical trial.