Immunotherapy and Hepatocellular Cancer: Where Are We Now?

Abstract

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.

Modeling the Synergistic Impact of Yttrium 90 Radioembolization and Immune Checkpoint Inhibitors on Hepatocellular Carcinoma

“…The results of this study predict several behaviors that have been clinically observed. Supplementary Figure S4 revealed that the benefit of adding Y90-RE to ICIs is increasingly improved in both targeted and non-targeted tumors than in patients who have only received a single treatment, as shown by previously small retrospective clinical trials [20,24,25]. The benefits of adding Y90-RE to ICIs are progressively enhanced in patients where less disease is left untreated.…”

“…The yttrium 90-radioembolization (Y90-RE) can stimulate the release of tumor antigens, which can activate T cells and enhance anti-tumor immunity [17], induce immunogenic cell death resulting in tumor regression in distant non-irradiated areas [18,19], and change the tumor microenvironment [20]. As Y90-RE has been shown to activate the immune system, further investigations are needed to evaluate the effectiveness and safety of Y90-RE and ICI combination treatment for HCC patients [21][22][23][24][25][26][27][28].…”

“…Despite the increasing number of clinical trials [21][22][23][24][25][26][27][28], there remains an unresolved concern with the combination of Y90-RE and ICIs regimens, as preclinical data suggests that strategic clinical studies on the type of agents, dosage, and sequence are required [29,30]. Mathematical modeling can be used in in silico virtual clinical trials to assist in the design of actual treatment because combining multiple modalities in clinical trials is a costly, timeconsuming, and labor-intensive form of research procedure.…”

Efficacy of radiofrequency ablation following transarterial chemoembolisation combined with sorafenib for intermediate stage recurrent hepatocellular carcinoma: a retrospective, multicentre, cohort study

“… 46 , 47 As the emergence of new multi-kinase inhibitors, immunotherapy, and the combination of the two, sorafenib was not the first choice for HCC patients worldwide. 48 , 49 However, we believe that our study could be applied not only for the sorafenib, but also for other multi-kinase inhibitors as Lenvatinib, and atezolizumab and bevacizumab.…”

A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis

“…The IMbrave150 study demonstrated a one-year survival rate of 67.2% with Ate/Bev compared to 54.6% with sorafenib [4]. Therefore, Ate/Bev therapy is recommended as the first-line therapy for advanced HCC, including for patients with portal vein tumor thrombosis (PVTT) [6][7][8][9].…”