Exploiting Tumour Ablation Histotripsy to Augment anti-cancer Immunotherapy in Hepatocellular Carcinoma

Tumour ablative procedures, such as microwave ablation and cryoablation, offer localised tumour control for hepatocellular carcinoma (HCC) but are limited by damage to the surrounding cirrhotic background liver. Histotripsy is a new non-invasive and highly targeted tumour ablation procedure under development by Histosonics, which stands to improve local tumour control whilst allowing patients with frail liver function to benefit from tumour ablation. Furthermore, understanding the immune response to histotripsy in HCC would enable targeted immunotherapy regimens to be developed to prevent the emergence of subsequent tumours, whilst protecting the frail background liver.
Objectives:
1. To characterise tumour immunology post-histotripsy in comparison to microwave- and cryoablation.
2. To design novel immunotherapy regimens post-ablation in HCC to induce robust and long-lasting anti-cancer immunity, whilst limiting side-effects to the frail background liver.
Experimental Approach:
The project will include the following experimental themes.
1. Tissue culture of primary HCC and non-malignant liver samples derived from patients undergoing hepatic surgery.
2. Flow cytometry assessment and plasma cytokine quantification of the temporal expression dynamics of immune checkpoint molecules on helper/cytotoxic T-cells, NK cells and antigen presenting cells, post-microwave-/cryo-ablation or histotripsy in HCC patients.
3. Assessment of the mechanisms of innate and adaptive immune anti-tumour effects post-histotripsy, by RNAseq, TCRseq and functional immune assays.
4. Optimisation of histotripsy-immunotherapy combinations and schedules in an in vitro T-cell priming model to test anti- cancer efficacy and background liver safety in non-malignant hepatocytes.
5. In vivo models of combination immunotherapy with tumour ablation in a bilateral flank syngeneic model of HCC.
6. Rational design of an early-phase clinical trial of combination immunotherapy with histotripsy in HCC.
Impact:
The Hope4Liver study is the first application of histotripsy in the UK. This project is the first to characterise the immunological sequelae of histotripsy, in comparison to conventional microwave- and cryoablation techniques. Successful completion of this project will directly define and refine a combination immunotherapy-histotripsy study in HCC. This therefore stands to be a practice-changing PhD project, defining and refining future tumour ablation-immunotherapy treatment regimens for patients with HCC and wider tumour types.