Immunotherapy and Hepatocellular Cancer: Where Are We Now?

Simple Summary HCC is the third-leading cause of cancer death worldwide. Prior to the immunotherapy era, treatment of advanced HCC was dominated by antiangiogenic tyrosine kinase inhibitors, with a quite poor prognosis with a median survival time of around one year. In this review, we aimed to elaborate on all the advances in immunotherapy in HCC from the indisputable first-line therapy atezolizumab-bevacizumab in advanced HCC to promising new strategies. We highlight the new standard of care in advanced HCC, namely, the combination of immune checkpoint inhibitors (ICI) durvalumab-tremelimumab, and also discuss the different combinations of antiangiogenic drugs with ICI. We develop how the combination of ICI with locoregional therapies could become a future treatment in early and intermediate-stage HCC, and, finally, we outline several new cell-therapy-based strategies to follow in the coming years. Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as "adjuvants" to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.