Bruno Sangro
Liver Unit, Clínica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.


The story of drug development for hepatocellular carcinoma (HCC) has been disappointing in the past eight years with many drugs failing in phase III trials. Very recently, an increased survival was shown in patients that tolerated sorafenib but eventually had radiological progression and were next treated with regorafenib 1. But no systemic therapy is effective in the adjuvant setting after resection or percutaneous ablation, or in combination with locoregional therapies such as TACE. On the other hand, immunotherapy has revolutionized the treatment of cancer. Over the last 5 years, immune-based therapies have shown that they can prolong patient survival in a wide variety of tumors and clinical scenarios. So-called immune checkpoint inhibitors are now approved for the treatment of refractory Hodgkin’s disease; metastatic non-small cell lung cancer or locally advanced urothelial cancer resistant to chemotherapy; metastatic melanoma naive to chemotherapy; recurrent squamous cell carcinoma of the head and neck; or for the adjuvant treatment of stage III melanoma. For a good reason, the American Society of Clinical Oncology has considered immunotherapy the Advance of the Year in 2015 and 2016.


Immune checkpoints are a specific subtype of membrane-bound molecules that provide fine-tuning of the immune response. They are expressed in different cell types involved in the immune response, including B and T cells, natural killer (NK) cells, dendritic cells, tumor associated macrophages, monocytes, and myeloid-derived suppressor cells (MDSC). The physiological function of these complexes is to prevent continuous T cell effector function upon initial stimulation and engagement of antigen-specific T cells. Thus, most of these molecules display an immunosuppressive activity that prevents uncontrolled T cell responses against infection and limit collateral tissue damage. The immune checkpoints most studied in human cancer are cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) 2. CTLA-4 is essential for the activation of helper CD4+ T cells and the priming phase of the immune response. Upon binding of its ligands, CTLA-4 decreases T cell activation following antigen presentation. CTLA-4 also plays a major role in the function of regulatory T cells (Treg), a subset of CD4+ T cells that inhibit the immune response. On the other hand, PD-1 is a key factor in the effector phase of the immune response. It is expressed by activated T and B cells and other cell types. Upon binding to its ligands (PD-L1 and PD-L2), PD-1 inhibits T cell activation and proliferation.

Monoclonal antibodies that bind these molecules and block their signaling are called immune checkpoint inhibitors. They release the brake that puts the immune response on hold and allow cytotoxic T cells to strike tumor cells. Other monoclonal antibodies may target different checkpoint molecules that provide positive signals for T cell or NK cell activation and proliferation, but they are at much earlier phases of clinical development.


Tremelimumab (a CTLA-4 blocking monoclonal antibody) was first evaluated in a small phase II trial that targeted patients with HCC and chronic HCV infection 3. Twenty-one patients with advanced disease were enrolled, including a significant proportion (42.9%) of patients in Child-Pugh stage B. Despite receiving a suboptimal dose of tremelimumab, a notable disease control rate of 76.4% was observed among 17 evaluable patients, including 3 partial responses and 4 prolonged (>6 months) stabilizations. Tremelimumab was well tolerated, with few patients experiencing grade 3 disabling adverse events (AE), even in the presence of liver dysfunction. In a second small pilot trial, incomplete tumor ablation using percutaneous radiofrequency (RFA) or transarterial chemoembolization (TACE) was combined in an attempt to enhance the effects of tremelimumab by inducing immunogenic tumor cell death 4. In this study, liver function was preserved in the most patients, all etiologies were included and the dose of tremelimumab was the standard. Nineteen patients were evaluable for response because they had measurable lesions that were not targeted by RFA or TACE. A disease control rate of 89% was reported, including 5 partial responses (26%) and 5 prolonged stabilizations. The median overall survival of 12.3 months compares well with placebo-treated patients in the second-line setting.

These encouraging signs of antitumor activity and good safety profile provided a strong reason to test PD-1 inhibitors [17]. Nivolumab (a PD-1 blocking monoclonal antibody) has been tested as first or second-line treatment in patients with advanced HCC across different etiologies (HCV infection, HBV infection, non-viral cirrhosis) 5. A dose-escalation cohort of 48 patients was followed by an expansion cohort of 214 patients treated with 3 mg/kg. Most patients had extrahepatic metastases (68%), and had received prior systemic therapy (76%), mainly Sorafenib. Treatment was by and large well tolerated with only 3% of patients discontinuing nivolumab due to treatment-related AE. Convincing signs of efficacy consisted in objective tumor responses in 15-20% of patients, which lasted for a median of 17 months. An additional 45% of patients had stable disease that was frequently durable too. These signs of efficacy were consistent with the most recently reported median overall survival of 28.6 months in the population naive to sorafenib, and 15.6 months in the population exposed to sorafenib (90% progressors) 6. This median survival compares well with any other phase 2 or 3 clinical trial of targeted agents including regorafenib, the first agent shown to prolong survival following sorafenib in a selected group of sorafenib-tolerant patients.


Encouraging as they are, the results of the reported trials pose a number of challenges. First, checkpoint inhibitors should be tested in the first line setting. Indeed, a large phase III trial is comparing nivolumab and sorafenib as first line therapy in advanced HCC and the results will likely be reported in 2018. Second, their activity has to be tested in the intermediate stage (in combination with intraarterial therapies that are the standard of care) and in the early stage (as adjuvant therapy after resection or ablation). Third, 30% to 40% of patients do not respond to these agents. The mechanisms of primary resistance are largely unknown 7 but combination strategies may work in these patients as we have learned in melanoma. Indeed, several combinations of checkpoint inhibitors with other therapies are being tested. They may be based on the potential additive effect of a therapy with a proven treatment benefit (TACE or sorafenib) or is being investigated (ramucirumab, cabozantinib), but they can also be based on exploiting synergistic effects (radioembolization, oncolytic virotherapy) or avoiding primary resistance (anti-CTLA-4 plus anti-PD1/PD-L1, tumor vaccines). Finally, evaluation of tumor response and selection of the best candidates based on easily accessible biomarkers remain a true challenge.


  1. Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56–66. doi:10.1016/S0140-6736(16)32453-9.
  2. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nature Reviews Gastroenterology & Hepatology 2015;12:681–700. doi:10.1038/nrgastro.2015.173.
  3. Sangro B, Gomez-Martin C, la Mata de M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81–8. doi:10.1016/j.jhep.2013.02.022.
  4. Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017;66:545–51. doi:10.1016/j.jhep.2016.10.029.
  5. El Khoueiry, Sangro…
  6. Crocenzi TS, El-Khoueiry AB, Yao T, Melero I, Sangro B, Kudo M, et al. Nivolumab in Sorafenib-Naive and -Experienced Patients With Advanced Hepatocellular Carcinoma: CheckMate 040 Study. Presented at the Annual Meeting of the American Society of Clinical Oncology 2017.
  7. O’Donnell JS, Long GV, Scolyer RA, Teng MWL, Smyth MJ. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treatment Reviews 2017;52:71–81. doi:10.1016/j.ctrv.2016.11.007.