Immunotherapy has emerged as an important treatment for liver cancer, particularly for hepatocellular carcinoma (HCC), the most common type of primary liver cancer. This approach harnesses the body’s own immune system to identify and eliminate cancer cells. Instead of directly attacking the tumor with chemotherapy or radiation, immunotherapy stimulates or restores natural defenses, enabling immune cells to fight the disease. It aims to achieve long-term control of the cancer and can be used to shrink advanced tumors or manage symptoms.
How Immunotherapy Targets Liver Cancer
Cancer cells, including those in the liver, possess mechanisms to avoid detection and destruction by the immune system. They can hide by exploiting natural “brakes” on immune responses, known as immune checkpoints. These checkpoints are proteins on immune cells that, when activated, prevent the immune system from attacking healthy tissues, maintaining self-tolerance.
Liver cancer cells manipulate these checkpoint proteins, such as PD-1 (Programmed Death-1) on T-cells and its ligand PD-L1 (Programmed Death-Ligand 1) found on tumor cells. When PD-1 on a T-cell binds to PD-L1 on a cancer cell, it sends an “off” signal, deactivating the T-cell and allowing the cancer to escape immune surveillance. Immunotherapy drugs, immune checkpoint inhibitors, block these interactions. By blocking these interactions, these drugs enable T-cells to reactivate, recognize cancer cells, and mount an anti-tumor response.
The liver itself presents a challenge due to its immune-suppressive microenvironment, which helps it tolerate substances from the digestive system. This environment can also inhibit the effectiveness of immunotherapeutic agents. Researchers are studying how to overcome this barrier to enhance treatment efficacy, often by combining immunotherapy with other therapies that can alter the tumor’s surroundings to become more permissive to immune attacks.
Approved Immunotherapy Approaches
Approved immunotherapy treatments for liver cancer primarily involve immune checkpoint inhibitors, often used in combination. A common first-line treatment for advanced or unresectable hepatocellular carcinoma (HCC) is the combination of atezolizumab and bevacizumab. Atezolizumab is an anti-PD-L1 antibody, blocking PD-L1 on tumor cells, enabling T-cells to attack. Bevacizumab, an anti-VEGF (Vascular Endothelial Growth Factor) therapy, prevents new blood vessel growth that tumors need to survive. It also helps immune cells infiltrate the tumor by normalizing tumor vasculature.
Other approved immune checkpoint inhibitors are also utilized in different treatment lines or patient scenarios. Nivolumab and pembrolizumab are both anti-PD-1 antibodies that block the PD-1 protein on T-cells, boosting the immune response against cancer. These drugs can be used for advanced liver cancer, sometimes after initial treatments like sorafenib.
Another approved combination is nivolumab with ipilimumab. Ipilimumab targets CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4), another immune checkpoint protein that regulates T-cell activity. This dual blockade aims for comprehensive immune system activation. These therapies are administered intravenously, through regular infusions at a hospital or clinic.
The Patient Treatment Journey
Immunotherapy for liver cancer is considered for patients with advanced or unresectable hepatocellular carcinoma (HCC) who have good liver function. It is used as a first-line systemic treatment, especially for those new to systemic therapies.
The treatment process involves regular intravenous infusions, with the frequency depending on the specific drug or combination. For instance, atezolizumab can be given every three weeks, sometimes subcutaneously, while nivolumab and ipilimumab might involve an initial four cycles of combination therapy followed by nivolumab alone. Infusions are received in a hospital or clinic setting.
While immunotherapy uses the body’s own defenses, it can cause side effects if the activated immune system targets healthy tissues. Common side effects include fatigue, weakness, skin rash, itching, nausea, diarrhea, loss of appetite, and muscle or joint pain. More serious side effects can involve inflammation of organs like the lungs, intestines, liver, kidneys, or hormone-producing glands. Patients should report any new or worsening symptoms to their medical team promptly. Early intervention, sometimes with corticosteroids, can help manage these immune-related adverse events.
Evaluating Treatment Response
Monitoring the effectiveness of immunotherapy for liver cancer involves a combination of methods to assess tumor changes and overall patient health. Regular imaging scans, such as CT (computed tomography) or MRI (magnetic resonance imaging), are performed to visualize the tumors and determine if they are shrinking, remaining stable, or growing. These scans provide visual evidence of the treatment’s impact on tumor size and spread.
Blood tests are used to monitor liver function and levels of tumor markers, such as Alpha-fetoprotein (AFP). Elevated AFP levels are common in HCC patients, and a decrease often indicates a positive response. While AFP is a useful marker, its levels can also be elevated in benign liver conditions, and some HCC patients may not have high AFP.
Pseudoprogression can occur with immunotherapy. This occurs when imaging scans initially show an apparent increase in tumor size or new lesions, which might be mistaken for disease progression. This temporary increase is due to an infiltration of immune cells into the tumor, causing swelling before the tumor begins to shrink. Distinguishing pseudoprogression from true disease progression is important. Doctors rely on continued monitoring, clinical improvement, and sometimes repeat scans to make an accurate assessment before changing treatment.