Developing and validating a preclinical platform for combining radiotherapy with immunomodulation in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the 3rd largest cause of cancer deaths worldwide and is a recognised cancer of unmet need. Whilst curative options exist, only a small minority of patients have these options.

The overwhelming majority of patients present with incurable late-stage disease and are limited to either transarterial chemoembolisation or systemic chemotherapy as palliative treatment options.

Stereotactic Ablative Radiotherapy (SABR) is an emerging therapy for a subset of HCC patients who are not eligible for resection or local treatments. SABR is delivered as a high dose, hypofractionated radiotherapy.

It has direct oncolytic activity and can stimulate low-level immunogenic cell death (ICD), which engages both the innate and adaptive arms of the immune response.

This immune engagement may break tumour-tolerance alone or potentially synergise with other therapies, particularly immunotherapy.

In HCC, SABR provides excellent local disease control, but alone does not sufficiently stimulate anti-cancer immunity to affect subsequent or residual disease.

Optimised immune engagement offers the promise to change this but requires a detailed understanding of how SABR works in synergy with immunomodulatory therapies and whether an enhanced ICD can be generated and promote anti-tumour immune responses.

Aims: Our aim is to test two specific therapeutic combinations including SABR, which are planned for imminent clinical trials, in a newly developed pre-clinical HCC platform.

Methods: Through collaboration between RadNet’s Glasgow and Leeds, we will combine in vitro assays with two murine transplant models (intrahepatic orthotopic and subcutaneous) in immunocompetent mice each with radiotherapy and chemotherapy.

We will combine SABR with oxaliplatin or combination VEGF inhibition + immunotherapy (modelling atezolizumab and bevacizumab standard of care) and monitor efficacy, immune responses and systemic cytokine and inflammatory profiles.

We will develop a range of orthotopic models using murine tumour organoids representing the major subtypes of human disease which may be used for precision medicine SABR studies in the future.

How the results of this research will be used: These studies will integrate with upcoming related clinical trials in HCC to demonstrate the human relevance of the model platform and explore treatment response biomarkers.

It will generate state-of-the-art models for the future and serve as a stepping stone for ensuing substantive grants to further optimise SABR-inclusive therapy combinations for precision medicine in HCC.

It will help guide the development of future clinical trials for multimodal HCC therapy and offers to unlock the potential for SABR to promote systemic anti-tumour responses in combination with immunotherapy.