What Is CTLA-4?

CTLA-4, officially named cytotoxic T-lymphocyte-associated protein 4, is a protein found on the surface of T cells involved in mesothelioma. These cells help the immune system fight off viruses, bacterial infections and cancers like mesothelioma. CTLA-4 acts like a brake, stopping the immune system from attacking healthy cells.

Mesothelioma cells can take advantage of these brakes to hide from the immune system. Blocking CTLA-4 helps release the “brakes,” making it easier for immune cells to find and attack mesothelioma. Because CTLA-4 acts as a brake, it’s called an immune checkpoint protein. Drugs that block CTLA-4 are called immune checkpoint inhibitors.

These drugs help the immune system find and fight cancer, which may help people with mesothelioma live longer. Targeting CTLA-4 with checkpoint inhibitors is a form of immunotherapy. New immunotherapy treatments offer some of the most promising options for mesothelioma today.

Common CTLA-4 Inhibitor Drugs

Yervoy (ipilimumab) is a common CTLA-4 inhibitor drug used to help the immune system fight mesothelioma. It’s FDA-approved only as a first treatment when combined with Opdivo (nivolumab). Yervoy is also a type of medicine called a monoclonal antibody, which is a lab-made protein that works like your body’s natural antibodies. Doctors usually give Yervoy every 6 weeks and Opdivo every 3 weeks.

Researchers are also testing new CTLA-4 drugs for mesothelioma. Imjudo (tremelimumab) is a CTLA-4 inhibitor usually paired with Imfinzi (durvalumab) in clinical trials, but it’s not yet FDA-approved for mesothelioma. Researchers are also studying new drugs like Cadonilimab (AK104), which targets both CTLA-4 and PD-1 (another checkpoint protein). Erfonrilimab, which targets CTLA-4 and PD-L1 (another checkpoint protein), is also being studied as a mesothelioma treatment.

How Does CTLA-4 Work for Mesothelioma?

Mesothelioma uses CTLA-4’s natural role as an immune system brake to protect itself from attack. Normally, CTLA-4 helps prevent T cells from overreacting and damaging healthy tissue. But mesothelioma tumors take advantage of this system, increasing CTLA-4 activity, which keeps T cells from recognizing and destroying cancer cells. This allows the tumor to hide from the immune system and continue to grow.

A recent study published in the Chinese Journal of Industrial Hygiene and Occupational Diseases found people with higher levels of CTLA-4 may have shorter survival times from mesothelioma. This is especially true in cases of pleural mesothelioma, the most common type of this cancer. 

That’s why drugs that block CTLA-4 are so important in mesothelioma treatment. In addition to boosting T cell activity, CTLA-4 inhibitors can also increase the number of T cells that enter the tumor and help trigger a broader immune response. This deeper immune activation is one reason why checkpoint inhibitors like Yervoy and Keytruda (pembrolizumab), which blocks the PD-1 protein,  are a key part of new mesothelioma therapies. 

Pastor and mesothelioma survivor Dr. Berlinda Love has begun treatment with CTLA-4 inhibitor Yervoy paired with Opdivo. She tells us her tumor has shrunk since beginning her immunotherapy regimen. “When we started out it was about 10 ten centimeters,” she shares. “The doctors were really impressed. It had shrunk down to about 5 centimeters.”

Illustration depicting an antibody inhibitor blocking the connection between a dendritic cell and the CTLA-4 receptor on a T cell.
The CTLA-4 blockade involves an inhibitor antibody that prevents the slowdown of anti-cancer T cell activation.

How CTLA-4 Inhibitors Are Used With Other Immunotherapies

Yervoy and Imjudo are usually combined with other drugs that target different checkpoint proteins to boost the immune system’s ability to fight mesothelioma. Yervoy is usually paired with Opdivo, which targets the PD-1 protein. Imjudo is usually paired with Imfinzi, which targets the PD-L1 protein. Active clinical trials for mesothelioma are looking at other pairing possibilities as well.

Research is key to finding better treatments for mesothelioma. For example, at the 2017 ASCO Annual Meeting, French researchers reported about 44% of mesothelioma patients had their cancer controlled with Opdivo alone. When Yervoy was added, that number increased to 50%. These encouraging results led to a larger clinical trial, and eventually, the FDA approval of the Yervoy and Opdivo combination for treating mesothelioma.

Mesothelioma Studies Featuring Imjudo (Tremelimumab)

  • Baylor College of Medicine: Studied whether Imjudo with Imfinzi before pleural mesothelioma surgery. Around 35% of those who got both had tumor shrinkage and side effects were manageable. 
  • Dana Farber Cancer Institute: This clinical trial tested Imjudo and Imfinzi as well. Improvements weren’t deemed significant enough to continue. 

Scientists continue to study CTLA-4 drugs like Yervoy and Imjudo with different drugs. They’re also being studied in combination with chemotherapy. Speak to your doctor or a Patient Advocate about clinical trials of CTLA-4 inhibitors you may be able to participate in.

Dr. Jacques Fontaine and Dr. Andrea Wolf
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Side Effects of CTLA-4 Inhibitors

When people with mesothelioma take CTLA-4 inhibitors, their immune system becomes more active, which can lead to side effects. These happen because the immune system may attack healthy tissues, not just cancer cells. Side effects from CTLA-4 inhibitors are usually different from those seen with chemo.

Common Side Effects of CTLA-4 Inhibitors

  • Changes in hormone levels, which may affect the thyroid or adrenal glands (endocrinopathies)
  • Cough or trouble breathing from lung inflammation (pneumonitis)
  • Diarrhea or stomach pain from inflammation of the colon (colitis)
  • Fatigue
  • Joint pain or muscle aches
  • Skin rash or itching (often the most common side effect)

Unlike chemo, which often causes nausea, hair loss and low blood counts, CTLA-4 inhibitors mainly cause side effects related to the immune system being overactive. Some side effects can be serious if they’re not treated quickly. It’s important to tell your doctor right away if you notice any new or worsening symptoms during treatment

A major difference between chemo and immunotherapy is symptom severity. Peritoneal mesothelioma survivor Randy Derouen tells us chemo gradually wore him down, “The good thing about immunotherapy is it doesn’t linger. I’d be fatigued with chemotherapy for 10 or 11 days.”

Common Questions About CTLA-4 Inhibitors

What is the difference between CTLA-4 and PD-1 inhibitors?

CTLA-4 and PD-1 inhibitors both help the immune system fight mesothelioma, but they work at different stages. CTLA-4 inhibitors help T cells, removing early “brakes” on the immune system. PD-1 inhibitors help T cells keep fighting at the tumor site, blocking signals cancer uses to shut them down. Doctors may use both drugs together to boost the immune response against mesothelioma.

Can CTLA-4 inhibitors cure mesothelioma?

CTLA-4 inhibitors can’t cure mesothelioma, but they can slow the cancer down to help some people live longer. These drugs help the immune system attack cancer cells and sometimes shrink tumors. Doctors often combine them with other mesothelioma treatments for better results. Researchers are still learning who benefits the most from CTLA-4 inhibitors. 

Are CTLA-4 inhibitors safe long-term?

CTLA-4 inhibitors are generally safe for many people, but they can cause serious side effects, especially with long-term use. These side effects happen when the immune system attacks healthy parts of the body. You may need to stop treatment or take steroids to manage symptoms. Inform your doctor about any side effects.

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