Immune Checkpoint Inhibitors for Mesothelioma

What Are Immune Checkpoint Inhibitors?

Immune checkpoint inhibitors target specific proteins on the surface of cancer cells called antigens. In turn, the inhibitory effects of tumor cells on immune cells are minimized. This allows the immune system to better control the cancer.

Clinical trials are testing these innovative drugs to discover if they could play a role in the treatment of mesothelioma.

Of these immunotherapy drugs, Keytruda, Opdivo and Yervoy have been approved to treat pleural mesothelioma by the U.S. Food and Drug Administration (FDA). Additionally, several ongoing clinical trials could lead to further approval.

A 2021 clinical research study treated peritoneal mesothelioma patients with a nivolumab and ipilimumab combination. The disease control rate was over 65%. The median overall survival was 19.1 months and 68% of patients survived for at least one year.

Research on mesothelioma has shown that several immune checkpoint inhibitors are effective against the asbestos-related cancer, especially Keytruda and the combination of Opdivo and Yervoy.

How Do Immune Checkpoint Inhibitors Work?

Checkpoint inhibitors are antibodies that block antigens on the surface of cancer cells or block proteins on immune cells called T cells. Antigens work like a mask to hide cancer cells from the immune system.

These antigens are also called immune checkpoints.

Drugs that inhibit checkpoint antigens effectively unmask cancer cells, allowing the immune system to recognize and attack the cancer.

The antigens that checkpoint inhibitors block include CTLA-4 and PD-L1.

Keytruda and Opdivo target PD-1, a checkpoint protein on the surface of T cells. PD-1 normally attaches to PD-L1. By preventing this interaction, T cells are not fooled into thinking cancerous cells are healthy, allowing for an immune response.

Out of all of these drugs, Keytruda is the most well-known. In 2015, former U.S. President Jimmy Carter said Keytruda put his malignant melanoma into remission.

Side Effects of Immune Checkpoint Inhibitors

Immune checkpoint inhibitors can cause side effects that are similar to other anti-cancer treatments such as chemotherapy and radiation therapy.

While some immune checkpoint inhibitor side effects overlap with those of more conventional treatments, the underlying cause is different.

Chemotherapy and radiation affect both cancerous and normal tissue. They work because they are much more damaging to rapidly dividing cancer cells than to normal cells.

Immune checkpoint inhibitors don’t damage cells directly. Instead, they allow immune cells to recognize cancer cells and destroy them.

Because these drugs “turn up” the immune system, they may cause the immune system to attack healthy cells and organs, too. This can lead to serious side effects.

How Common Are Serious Side Effects?

These serious side effects can occur in up to 30 percent of patients receiving checkpoint inhibitors. If they occur, they require immediate attention.

According to a 2018 Journal of the American Medical Association article, autoimmune complications of these therapies can affect a variety of tissues and organs.

Skin

Autoimmune skin side effects are the most common, affecting up to 30 percent of people.

Typical treatments for skin issues include topical steroids and antihistamines for mild cases. Oral steroids can be used to manage more serious skin side effects.

Gastrointestinal Tract

Autoimmune colitis — an inflammation of the lining of the colon — occurs in approximately 25 percent of patients taking Yervoy and less than 5 percent of people receiving anti-PD-1 or anti-PD-L1 single-drug therapy.

This side effect can be life threatening, so if you experience any changes in bowel habits, report this to your oncologist right away.

Mild cases can be managed with hydration and anti-diarrheal medication. More severe cases always require oral steroids.

This is different from diarrhea because of cytotoxic chemotherapy, which can be managed with oral hydration, electrolytes and antidiarrheal drugs.

Lungs

Between 2 to 5 percent of people treated with immune checkpoint inhibitors experience life-threatening pneumonitis or inflammation in the lungs.

Symptoms of pneumonitis include a dry cough, shortness of breath and low blood oxygen levels (hypoxia). These side effects are similar to pleural mesothelioma symptoms.

If you experience changes in your breathing when taking an immune checkpoint inhibitor, tell your oncologist immediately.

Endocrine System

The endocrine system includes glands that excrete hormones, which are found in many parts of the body. Symptoms of these autoimmune complications include fatigue, low blood pressure and headaches.

Endocrine complications typically are permanent and are managed with replacement hormones.

Liver, Heart & Nervous System

Immune checkpoint inhibitor complications involving the liver, heart and nervous system are rare.

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Clinical Trials Testing Mesothelioma Immune Checkpoint Inhibitors

The majority of mesothelioma clinical trials testing these drugs involve two immune checkpoint inhibitors. Combining drugs that target different antigens has a synergistic effect.

Some trials combine immune checkpoint inhibitors with chemotherapy or a mesothelioma vaccine.

Yervoy and Opdivo

Positive results from phase I and phase II trials of Yervoy and Opdivo in mesothelioma patients has led to a phase III clinical trial.

This is significant because phase III trials for mesothelioma are rare. It isn’t common for a therapy to work well enough in a phase II mesothelioma trial to warrant further study. Researchers have high hopes for this study.

Imfinzi and Tremelimumab

Trials of Imfinzi and tremelimumab in mesothelioma patients began in 2016 and 2017. These trials are too new to produce results.

However, in 2015, an Italian clinical trial that combined these drugs proved clinical activity in mesothelioma, which means the study proved these drugs are effective but did not prove whether the drugs improved survival.

Imfinzi and Chemotherapy

In 2017, the Seattle Cancer Care Alliance opened a phase II clinical trial combining Imfinzi with the chemotherapy drugs cisplatin and pemetrexed (Alitma).

Keytruda and Mesothelioma Vaccine CRS-207

In 2017, the Moffitt Cancer Center in Tampa, Florida, opened a phase II clinical trial combining Keytruda with the mesothelioma vaccine CRS-207. The trial is available at five other cancer centers in the U.S.