T cells engineered to carry a high-affinity HBV-specific T cell receptor: a potent weapon against advanced HBV-related HCC

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death worldwide, and the incidence is predicted to further increase substantially within the next 20 years in all regions of the world.1 HCC surveillance in individuals at risk, including patients with liver cirrhosis as well as patients with HBV infection or metabolic dysfunction associated steatohepatitis, aims at early diagnosis of HCC, allowing for curative treatment such as resection or liver transplantation. In addition, locoregional therapies such as radiofrequency ablation, microwave ablation, transarterial chemoembolisation or radiotherapy are valuable treatment options in intermediate cancer stages. A large proportion of patients, however, are diagnosed in an advanced cancer stage, with multiple liver lesions or even extrahepatic metastases. These patients require systemic therapy. During the last few years, checkpoint-inhibitor based immunotherapy has become the first-line therapy for advanced HCC.2 While immunotherapy has prolonged survival in approximately one-third of patients substantially, a large proportion of patients has little benefit from immunotherapy. Unfortunately, adequate predictors of treatment response are still lacking. Possible reasons for inadequate response to immunotherapy may include non-canonical pathways of exhaustion of tumour-specific T cells that cannot be reverted by checkpoint inhibitors, as well as insufficient priming of tumour-specific T cells due to the immunotolerant liver environment or additional immune-evasive strategies of the tumour.3–5 These limitations of checkpoint-inhibitor-based immunotherapy may be circumvented by T cell engineering, redirecting autologous bulk T cells either to express a tumour-specific T cell receptor (TCR) or a chimeric antigen receptor (CAR). Engineered TCR T cells have the limitation that they depend on presentation of (tumour) antigens on specific human leucocyte antigens (HLA). For example, TCR …