Immunotherapy for hepatocellular carcinoma: the next evolution in expanding access to liver transplantation

Immunotherapy has revolutionized treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in early- to intermediate-stage HCC in combination with surgical or locoregional therapies have recently reported positive results, and multiple other phase III trials in the same patient population are currently in process. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarize key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients.