In 2018, there were an estimated 840,000 new cases of liver cancer worldwide, making it the fifth-most common cancer diagnosed in men and the ninth-most common in women. In the United States alone, there were an estimated 42,000 people were diagnosed with liver cancer and 30,000 deaths due to the disease. The most common form of liver cancer is hepatocellular carcinoma (HCC), which can be caused by infection with the hepatitis B or C viruses as well as cirrhosis of the liver resulting from chronic and excessive alcohol use. In cases of localized cancer that remains confined to the liver, the five-year relative survival rate is roughly 31 percent; however, that survival rate drops to about 11 percent as liver cancer spreads to nearby organs and the lymph nodes, and to 3 percent once it has metastasized to distant organs. In light of these facts, better treatment options are urgently needed for patients with liver cancer, especially those with advanced diseases.
Immunotherapy treatments that unleash the immune system’s ability to fight cancer offer a promising new avenue through which doctors can potentially improve outcomes for patients with liver cancer. Already, two immunotherapies have been approved by the U.S. Food and Drug Administration (FDA) for subsets of patients with advanced liver cancer. Additionally, clinical trials are exploring other promising options for these patients.
To better understand the current immunotherapy efforts in liver cancer, we spoke with liver cancer expert Bruno Sangro, M.D., Ph.D. Dr. Sangro is the director of the Liver Unit at Clínica Universidad de Navarra and a professor of medicine at the University of Navarra School of Medicine in Spain, and a senior researcher in the National Biomedical Research Network Center for Liver and Digestive Diseases. Among other clinical responsibilities, Dr. Sangro is an investigator on the pivotal phase III HIMALAYA clinical trial that is evaluating a combination immunotherapy in patients with previously untreated, inoperable liver cancer (HCC).
Where does immunotherapy fit into the current treatment landscape for patients with liver cancer?
Two immune checkpoint inhibitors, nivolumab and pembrolizumab, which target the PD-1/PD-L1 pathway, have been approved in several countries for the treatment of patients with advanced liver cancer who have progressed after they were treated with sorafenib chemotherapy, the standard-of-care drug typically used to treat these patients. Now we are eagerly awaiting the result of large phase 3 trials that will answer the question of whether checkpoint inhibitors targeting the PD-L1 and CTLA-4 immune checkpoint pathways alone or in combination could be a better option than sorafenib as first-line treatment or not. If so, this would pave the way for liver cancer patients to be treated with immunotherapy without having to first undergo chemotherapy.
Are there any side effects associated with these immunotherapies for liver cancer? If so, are they manageable?
Immunotherapies are by and large well tolerated and we have observed that the toxicity profile in liver cancer is not different from that observed in other types of tumors. This includes liver toxicity, too. Most patients with liver cancer also have cirrhosis due to chronic viral infections or other causes so in the beginning we were concerned about liver toxicities that could have caused more severe problems. That was not the case. Only a minority of patients have liver toxicities and they usually resolve after treatment withdrawal or with the use of immune modulators. Only in exceptional cases do patients have to abandon treatment because of severe liver-related side effects, also known as adverse events.
In other cancer types, combining PD-1/PD-L1 checkpoint immunotherapies with other treatments, including chemotherapy and other immunotherapies, have helped improve response rates for patients. Are there any promising immunotherapy combinations currently being evaluated in clinical trials for liver cancer?
Between 30 and 40 percent of liver cancer patients are primarily resistant to checkpoint inhibitors given as a single agent, or monotherapy. For these patients, combinations with other therapies should be explored. Many clinical trials are testing combinations of PD-1/PD-L1, including with other immunotherapies that target the CTLA-4 immune checkpoint, tyrosine kinase inhibitors (TKIs) with known efficacy in liver cancer, and other targeted agents that might have synergistic effects. The potentially enhanced activity of such combinations may also benefit patients that achieve tumor shrinkage with PD-1 checkpoint blockade since increasing the depth of response may well lead to more prolonged survival. On the other hand, we have to face that drug combinations could increase toxicity and add to the financial burden of receiving such treatments.
Biomarkers can provide valuable information about patients’ tumors and even help doctors predict which patients are more likely to benefit from immunotherapy. In the context of liver cancer, which biomarkers currently appear to offer the most value for doctors and patients, and how are they being used to improve treatment-related decisions in the clinic today?
We still don’t know much about the factors that may help us select the best candidates for immunotherapy in liver cancer. Neither the cause of liver cancer nor levels of a tumor marker called alpha-fetoprotein appear to influence outcome. Tissue and blood biomarker analysis in the main clinical trials have not been reported yet. In particular, we don't know if PD-L1 expression in the tumor microenvironment or mutational tumor burden, which have been associated with immunotherapy patient outcomes in other types of cancer, could help us in this important task. We have some indications that tumor infiltration by immune cells called effector T cells may be relevant for the activity of CTLA-4 inhibitors but the data need to be confirmed.
Cellular immunotherapies, such as CAR (chimeric antigen receptor) T cells, have shown remarkable benefits over the past few years for patients with blood cancers like leukemia and lymphoma. Could you talk about some of the cellular immunotherapies in clinical trials for liver cancer patients as well as some of the challenges that are being addressed in order to improve their effectiveness?
Solid tumors run behind blood cancers in this regard. Nevertheless, the field is slowly moving forward. A clinical trial is testing autologous T cell receptor (TCR)-engineered T cells that can recognize alpha-fetoprotein in patients that express high levels of this oncoprotein. A second trial running in China is testing CAR-T cells able to recognize glypican-3, a membrane molecule that is expressed in most hepatocellular carcinoma cells that we use for pathological diagnosis. An important question with these therapies is what the impact of immune cell depletion that occurs with some forms of chemotherapy would be on cirrhotic patients. Previous experience says it should be manageable but we have to pay close attention.
Looking beyond checkpoint and cellular immunotherapies, what other immune-based approaches are on the horizon that you’re hopeful about? Furthermore, what are the most pressing questions that need to be answered in order to enhance today’s immunotherapies as well as develop the improved immunotherapies of tomorrow?
It’s hard to imagine that checkpoint inhibition would not be the backbone of any successful future immunotherapy for liver cancer. We have to build on the good results we have already observed. A particularly appealing approach is to combine checkpoint inhibitors with treatments that may overcome tumor-induced immunosuppression or increase the ability of the host cells to react against tumor antigens. In this line, we are conducting interesting research with vaccination platforms or the use of locoregional therapies such as radiation that may cause tumor cell death that alerts the immune system to the presence of cancer. Investigator-sponsored clinical trials play a pivotal role in defining new pathways of therapeutic development.
Certainly, the most pressing question that needs to be answered is what are the mechanisms of resistance to checkpoint inhibition and how could we use this knowledge to improve therapies and determine which patients are likely to benefit from such treatment.
Finally, can you talk a little bit about the importance of clinical trials when it comes to advancing the field and ensuring that the most promising approaches are made available for patients with liver cancer?
Clinical trials are behind the prolonged survival that some patients with liver cancer enjoy today. Relevant, well-designed, and reliable trials are essential to the advancement of cancer patient care. We nevertheless face a number of problems in this field. With so many agents and strategies, investigators should play a key role in promoting and selecting those trials that have a higher chance of improving patient outcomes. Regulatory authorities should be attentive to the rapidly changing environment and promote the discussion about new trial design that would save the money and time invested in failing strategies. And the general public should be informed about the relevance of clinical trials and how people can help other people win the battle against cancer.
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