Gastroenterology

Gastroenterology

Volume 156, Issue 2, January 2019, Pages 510-524
Gastroenterology

Review
Targeted and Immune-Based Therapies for Hepatocellular Carcinoma

https://doi.org/10.1053/j.gastro.2018.09.051Get rights and content

Treatment options for patients with hepatocellular carcinoma are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with hepatocellular carcinoma, as first- and second-line therapies, and are awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discuss the future of these strategies for liver cancer.

Section snippets

Nonsurgical and Nontransplant-Based Therapies

Locoregional therapies include percutaneous local ablation, chemoembolization, radio-embolization, and external radiation therapy; they are the most common first-line treatments, although 50% of patients receive systemic therapies at some point during disease progression.4 Their efficacy is limited by tumor size and location. Percutaneous local ablation is the only curative locoregional therapy—subtypes include percutaneous ethanol injection, radiofrequency ablation (RFA), microwave ablation,

Prospects for Locoregional Therapies

Locoregional therapies are important in management of patients with HCC. The SARAH and SIRveNIB trials did not find TARE to increase survival times of patients compared with systemic therapy.10, 11 In contrast, a recent study reported an overall survival time of 26 months for patients treated consecutively with the tyrosine kinase inhibitors sorafenib and then regorafenib.12 These findings indicate that targeted therapies could be as effective as locoregional therapies. There have been attempts

First-Line Treatments

Sorafenib was the only drug approved for the systemic treatment of patients with HCC until 2017. It is a tyrosine kinase inhibitor that blocks the activities of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and Raf family kinases. It extends the mean overall survival time of patients with advanced HCC by 2.8 months.15 Similar results have been reported in an Asian patient population.16 After positive results from a pivotal phase 3 trial (Study

Second-Line Therapies

Regorafenib is an oral multi-kinase inhibitor that blocks the activity of kinases that promote angiogenesis, cell proliferation, metastasis, and tumor immunity.38, 39 Its chemical structure is similar to that of sorafenib—it differs in only 1 fluorine carbon atom in the central phenyl ring. It was tested in 573 patients who had tolerated sorafenib but still had tumor progression, from 2013 through 2015. Patients who received regorafenib had increased median times of overall survival (10.6 vs

Nonimmune-Based Agents

HCCs are recognized as hypervascular tumors.40, 41 In adults, angiogenesis occurs primarily during tumor development42 and involves multiple signaling pathways.43 Signaling is mediated by factors, such as VEGF, platelet-derived growth factor, and platelet-derived growth factor, produced by tumor cells, immune cells, and/or stromal cells.44, 45 Agents designed to block the activity of VEGF (ramucirumab, bevacizumab and cabozanitinib) and platelet-derived growth factor (MEDI-575 and preretinoin),

Immune Checkpoint Inhibitors

Immune checkpoints are pathways that inhibit the immune response to maintain self-tolerance and regulate the duration and amplitude of immune responses. Tumors activate immune checkpoint mechanisms to suppress the antitumor immune response. Binding of checkpoint proteins such as the CD274 molecule (programmed death ligand 1 [PDL1]) on tumor cells to programmed cell death 1 (PD1) on T cells keeps T cells from killing tumor cells. Therefore, checkpoint inhibitors are being tested in clinical

Combining Immune and Targeted Therapies

Combination studies evaluating combined anti-CTLA4 and anti-PD1 or anti-CTLA4 and anti-PDL1 are underway.62 Antibodies against other immune checkpoint regulators, such as lymphocyte activating 3, B- and T-lymphocyte attenuator, and trypsin inhibitor 3, are in clinical trials and some are being evaluated in patients with HCC (NCT03005782, NCT03489369, NCT01968109, NCT03250832, NCT03489343, NCT02817633, and NCT03099109).

Other strategies to increase the antitumor immune response involve agents

Future Directions

With the recent approval of new drugs for the treatment of patients with HCC, several positive results from phase 3 studies, and advances in immunotherapy, there are more treatment options for patients with liver cancer. Trials are underway that combine targeted therapies with immune-based therapies (Figure 1). However, more studies are needed to identify the best combinations and to determine their optimal timing, such as adjuvant therapies or first-line or second-line agents. Advances in DNA

Acknowledgments

Author contributions: Tim F. Greten, Chunwei Walter Lai, Guangfu Li, and Kevin F. Staveley-O’Carroll performed the literature search and wrote the manuscript.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Tim F. Greten is supported by he Intramural Research Program of the National Cancer Institute, National Institutes of Health (ZIA-BC 011343). Chunwei Walter Lai is supported by the intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Kevin F. Staveley-O’Carroll and Guangfu Li are supported by the National Cancer Institute, National Institutes of Health (R01 CA164335).

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