While chemotherapy works directly on tumors to kill cancer cells, immunotherapy works by “revving up” a patient’s own immune system to attack the cancer. It is another relatively new treatment that strives to improve the immune system’s ability to identify and destroy cancer cells. Immunotherapy has been used in many different types of cancer, including liver cancer.

In this video from a 2019 Cancer Research Institute Immunotherapy Patient Summit, Dr. Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive Cancer Center (and member of the FCF Medical & Scientific Advisory Board), gives an overview of the emerging role of immunotherapy in cancer treatment

There are several different types of immunotherapies that are being developed for many different diseases. These include:

  • Checkpoint inhibitors – drugs that block proteins that stop the immune system from recognizing and attacking the cancer cells
  • Adoptive cell transfer therapy – a treatment that engineers a patient’s own immune cells to better recognize the cancer, grows them in a lab, and reinserts them in the body to attack the cancer. One type of adoptive cell therapy that has already made strong progress in certain types of blood cancers is CAR-T (chimeric antigen receptor T cell) therapy.
  • Monoclonal antibodies (MABs) – immune system proteins created in the lab that are designed to bind to specific targets on cancer cells. While some MABs are considered “targeted therapy”, some can be used to mark cancer cells so that they will be better seen and destroyed by the immune system.
  • Treatment vaccines – vaccines which cause a person’s immune system to attack cancer cells.
  • Immune system modulators – naturally occurring proteins that enhance the body’s immune response against cancer.

Immunotherapies used as treatment for FLC

Of those five types of immunotherapy, three are currently being used to treat FLC, including checkpoint inhibitors, monoclonal antibodies and immune system modulators. In each of these immunotherapy categories, patient treatment with at least one drug is already underway.

An important function of a person’s immune system is keeping their immune cells from attacking normal cells in the body. T cells (a main type of immune cell that kill virus-infected cells and cancer cells) have proteins on them that are used to turn on or off an immune response. These are called checkpoints. Cancer cells can sometimes use these checkpoints to avoid being attacked by the immune system. Drugs that block these checkpoint proteins are called checkpoint inhibitors.

This video from the National Cancer Institute give a general overview of how immune checkpoint inhibitors work

PD-1 is one type of checkpoint protein on T cells. When PD-1 attaches to PD-L1, a protein on other cells in the body, it acts as an “off switch” that tells the T cell to leave the other cell alone. If cancer cells contain large amounts of PD-L1, they can essentially remain hidden from T cells. Drugs that can block the binding of PD-L1 and PD-1 can therefore boost an immune response against cancer cells. CTLA-4 is another type of checkpoint. CTLA-4 and PD-1 play different roles in inhibiting immune responses, including responses to tumors. CTLA-4 is thought to regulate T-cell proliferation early in an immune response, whereas PD-1 suppresses T cells later in an immune response, primarily in peripheral tissues.

Several checkpoint inhibitors are currently being used to treat liver cancer and FLC. These include:

  • Nivolumab (Opdivo) – a checkpoint inhibitor that targets the PD-1/PD-L1 pathway. In 2017, nivolumab was approved by the FDA for patients with advanced liver cancer. In 2020, the combination with ipilimumab was also approved for patients with HCC that were previously treated with sorafenib. (See the combination therapy discussion below.)
  • Pembrolizumab (Keytruda) – a checkpoint inhibitor that targets the PD-1/PD-L1 pathway. In 2018, pembrolizumab was approved for patients with advanced liver cancer who were previously treated with sorafenib. (See the clinical trials page for more information about a pediatric clinical trial using pembrolizumab).
  • Atezolizumab (Tecentriq) – a checkpoint inhibitor that targets the PD-L1 pathway. In 2020, atezolizumab plus bevacizumab (Avastin), was approved as a first-line treatment for some patients with advanced liver cancer.
  • Ipilimumab (Yervoy) – a checkpoint inhibitor that targets the CTLA-4 pathway. Ipilimumab in combination with nivolumab, was approved in 2020 for patients with advanced, previously treated liver cancer.

Three papers have been recently published about the use of checkpoint inhibitors in FLC:

  • Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors (click here to read a summary) determined that approximately 13 – 15% of FLC patients achieve a partial clinical response from ICI therapy.
  • Fibrolamellar carcinoma transcriptomic-based treatment prediction: complete response after nivolumab and ipilimumab (click here to read a summary) describes a case study of a patient achieving full remission after treatment with a dual ICI approach.
  • Using dual checkpoint blockade to treat fibrolamellar hepatocellular carcinoma (click here to read a summary) outlines another case from Germany of a patient achieving full remission after dual ICI treatment.

Many immune system modulator drugs are based on cytokines – proteins made by white blood cells. One in particular, interferon alfa is sometimes used in the treatment of fibrolamellar. Interferon alfa can enhance a patient’s immune response to cancer cells by causing some white blood cells to become active and to attack the cancer. It can also encourage cancer cells to send out chemicals that attract immune system cells to them.

For many years, interferon alfa has been administered to patients in conjunction with the chemotherapy drug, 5-FU. Interferon alpha-2B is also part of the newer “triple therapy” – nivolumab/5-FU/interferon alfa-2b – that has been given to some FLC patients. This “triple therapy” is currently being used as a treatment at some institutions and is currently the subject of a clinical trial (see the clinical trials page for more information).

Therapeutic cancer vaccines work by stimulating the immune system to attack tumor cells. They are made from cancer cells, parts of cancer cells, or proteins from the surface of cancer cells and are designed to help the body to recognize the disease and fight it.

In this video, Dr. Mark Yarchoan from Johns Hopkins describes the use of therapeutic vaccines to treat cancer

Research in this area is at an early stage and vaccines are only available today as part of a clinical trial. There currently are two clinical trials underway to assess the effectiveness of a peptide vaccine that targets the unique fusion protein in FLC – one at Johns Hopkins and another in Germany. In the Hopkins trial, a peptide vaccine is used in combination with Opdivo and Yervoy; in the trial in Tübingen, Germany, a peptide vaccine in used in combination with Tecentriq. Please see the clinical trials page for more information about these clinical efforts.

This linked journal article published in Nature Communications in October 2022 summarizes a case result of a liver transplant patient treated with a peptide vaccine at University Hospital Tübingen. Results from the clinical trial at Johns Hopkins should be released at the Society for Immunotherapy of Cancer’s (SITC) annual meeting in November 2023.

Combination therapies including immunotherapy

Across many cancers, there has been a lot of research conducted investigating the benefit of combining immunotherapy treatments (especially checkpoint inhibitors) with other therapies, including chemotherapy, targeted therapy and radiation therapy. It is thought that the breakdown of tumor cells by other drugs and localized treatments could help immune cells recognize a cancer as foreign, and therefore improve the effectiveness of the immunotherapy. Alternatively, the additional treatments could potentially drive additional immune cells to penetrate the tumor and therefore enhance the impact of the immunotherapy treatment.

Notable immunotherapy combination treatments under investigation for FLC include:

  • Nivolumab, plus 5-fluorouracil (5-FU) and interferon alpha-2b. Many fibrolamellar patients have already been prescribed this “triple therapy” at some institutions. See the clinical trials page for more information about a clinical trial that is trying to understand the interactions of this combination and the value of sequencing the drugs.
  • Ipilimumab plus nivolumab (approved in 2020 for the treatment of HCC).
  • Atezolizumab plus bevacizumab (approved in 2020 for the treatment of HCC).
  • Nivolumab plus lenvatinib.

Please note: The Fibrolamellar Cancer Foundation does not provide medical advice or recommend any specific organizations or services. We provide website users with information to help them better understand their health conditions and current approaches to the diagnosis and treatment of FLC. Always seek the advice of your physician or other qualified healthcare providers.