Table 2.

Classes of Therapies in Combination Therapy With Checkpoint Inhibitors in Hepatocellular Carcinoma

Class of Therapies	Examples of Combinations Currently Tested	Rationale
Combination with another checkpoint inhibitor	Anti-PD-1/PD-L1 and CTLA-4; -PD-L1 and TIM-3; -PD-L1 and LAG-3	Inhibition of alternate inhibitory pathway in immune cells; increase number of activated CD8+ T cells156
Combination with multikinase inhibitor or antiangiogenic drug	Anti-PD-1/PD-L1 with sorafenib; Anti-PD-1/PD-L1 with levantinib; Anti-PD-L1 and apatinib; Anti-PD-L1 with bevacizumab (IMbrave150)	Reduces immunosuppressive Tregs and MDSCs; antiangiogenic properties may increase tumor hypoxia and enhance expression of immune checkpoint molecules157
Combination with local therapy	Anti-PD-1 with TACE; Anti-CTLA-4 with RFA/TACE	Enhanced immune cell activation and recruitment158; upregulation of soluble PD-L1159
Combination with oncolytic virus	Anti-PD-1 with Pexa-Vec (JX-594)	Promotion of NK and T-cell tumor infiltration160
Combination with polypeptide	Anti-PD-1 with DSP-7888 (NCT03311334)	Polypeptide HCC vaccine to expand preexisting neoantigen-specific T-cell population
Combination with antibiotics	Anti-PD-1 with vancomycin and tadalafil (NCT03785210)	Oral antibiotic alters gut commensal bacteria inducing antitumor effect