Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets

Abstract

Although hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

“…Many mAbs are now available for cancer therapy use and have been approved for the treatment of various cancers, improving the survival and quality of life for patients. However, a negative effect of this treatment is that the PD-1/PD-L1 blockade may induce autoreactive T cells responsible for immune-related adverse effects (irAEs) [58]. In addition, recent evidence suggests that one of the molecular mechanisms responsible for the failure of PD-1/PD-L1 targeted therapy is the presence of extra-tumoral PD-L1 contained in exosomes, small nanoparticles released from the surface of both normal and tumor cells containing biologically active molecules [59].…”

Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study

“…[8][9][10][11][12] In the last 10 years, the rapid development of systemic therapy [tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)] has shown dramatic therapeutic effects and brought new hope to the treatment of patients with unresectable HCC (uHCC). 13 Moreover, combination therapy has shown better trend in tumor response and survival outcomes with monotherapy. [13][14][15][16][17][18] Combined therapy with different mechanisms of action may improve outcomes.…”

“…13 Moreover, combination therapy has shown better trend in tumor response and survival outcomes with monotherapy. [13][14][15][16][17][18] Combined therapy with different mechanisms of action may improve outcomes. At present, most of the combination therapies are dual therapies: combinations of TKIs and ICIs, combinations of two ICIs, combinations of TKIs and TACE, combinations of ICIs and cytotoxic agent, or a combination of TKIs and hepatic arterial infusion chemotherapy.…”

Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects

“…Oncolytic viruses are viral particles engineered to lyse tumor cells and induce anti-tumor immune responses. JX-594 (Pexa- Vec) is currently the main oncolytic virus used in HCC clinical trials (115). JX-594 is a vaccinia virus with disruption of the viral thymidine kinase (TK) gene for cancer selectivity and insertion of human granulocyte-macrophage colony-stimulating factor (hGM-CSF) for immune stimulation (116).…”