Combinatorial immunotherapy of sorafenib and blockade of programmed death-ligand 1 induces effective natural killer cell responses against hepatocellular carcinoma

Abstract

Sorafenib, a multi-tyrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC). Herein, we report that the combinatorial therapy of sorafenib and anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) can be implemented with good results for HCC. Cancer mouse models were used to evaluate therapeutic efficacy and examine the immunologic mechanisms of the sorafenib/anti-PD-L1 mAb therapy. The combined administration of sorafenib and anti-PD-L1 mAb into tumor-bearing mice generated potent immune responses resulting in the complete eradication or remarkable reduction of tumor growth. In some instances, the sorafenib/anti-PD-L1 mAb therapy induced long-lasting protection against tumor rechallenges. The results indicate that NK cells but not CD4T cells or CD8 cells mediated the therapeutic efficacy of this combinatorial therapy. The overall results suggest that immunotherapy consisting of the combination of sorafenib/anti-PD-L1 mAb could be a promising new approach for treating patients with HCC.

Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma

“…This may allow the formation of a niche for NK cell expansion or may augment NK cell activity. For instance, sorafenib, a kinase inhibitor used to treat HCC, can inhibit the shedding of MICA from HCC cells [28] and combinatorial immunotherapy of sorafenib with blockade of programmed death-ligand 1 generates potent immune responses that can result in NK cell-mediated eradication or reduction of tumor growth in tumor-bearing mice [29].…”

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

“…Therefore, combination of immunotherapeutic drug and sorafenib has recently emerged as a new treatment method for advanced HCC. Wang et al reported that this combinatorial approach resulted in blockade of programmed death-ligand 1 (PDL1) and sequential effective natural killer cell responses against hepatocellular carcinoma [155]. Chen et al reported that combination of anti-PD-1 immunotherapy with sorafenib showed efficacy concomitant with targeting of the hypoxic and immunosuppressive microenvironment in mice model [156].…”

Combinational immune-cell therapy of natural killer cells and sorafenib for advanced hepatocellular carcinoma: a review

“…Combinational immunotherapy using sorafenib is a very novel approach applied for treatment of HCC patients. Therapeutic efficacy of sorafenib and anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) has been shown to result in a considerable reduction of tumor growth by induction of effective NK cell responses against HCC [ 27 ]. As a result of in vitro and in vivo experiments on HCC patients treated with the combination of sorafenib and erlotinib (inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase), no additional effect was observed and the survival rate of patients with advanced HCC did not improve [ 28 , 29 ].…”