Mesothelioma is a rare type of cancer that develops after contact with asbestos fibers. At this time, unfortunately there is no cure. The average survival rates reported by the American Cancer Society are low: less than two years for those diagnosed early and just one year for those diagnosed at Stage IV. When a new treatment comes along, the mesothelioma patient community greets it with understandable excitement. This is just what happened when tremelimumab mesothelioma immunotherapy showed positive results in a 2015 study.
The study of tremelimumab mesothelioma immunotherapy continues. More recent outcomes have yielded more complex results. Mesothelioma is a complex disease. The better you understand this uncommon cancer, the better you’ll be able to understand and manage your treatment.
Asbestos fibers are thin and sharp. When this mineral is disturbed, such as during construction and home renovation or during manufacturing with asbestos, tiny particles can become airborne. People who worked in boiler rooms, in construction jobs, on ships, or in other places where asbestos was used may have unwittingly inhaled asbestos fibers. And often, they brought those fibers home on their clothes and in their hair, contaminating their cars on the way, and then their homes, where fibers lodged in furniture, carpets, drapes etc to be put back in the air as family members moved around.
Mesothelioma is a cancer that originates in the mesothelium. The mesothelium is a delicate and flexible tissue that forms a lining around some of your internal organs. Asbestos fibers tend to lodge in and cause irritation in these tissues over time. If you inhale toxic asbestos fibers, it can take as long as several decades for mesothelioma to develop.
Asbestos can also cause other diseases, such as lung cancer.
There are four known types of mesothelioma:
- Pleural mesothelioma: The most common way to take in asbestos fibers is by breathing them in, so the first point of contact is your lungs. Almost three quarters of the people who develop mesothelioma get the pleural form. This affects the pleura or the lining around your lungs.
- Peritoneal mesothelioma: The second most common form of mesothelioma, this type affects the peritoneum. This is the lining that protects the organs in your abdomen. About 20 percent of mesothelioma patients have peritoneal mesothelioma.
- Pericardial mesothelioma: The pericardium is the lining around your heart that also provides lubrication so your heart can beat without friction. Pericardial mesothelioma is quite rare.
- Testicular mesothelioma: This is the rarest form of mesothelioma. It accounts for less than one percent of the roughly 3,000 people diagnosed with mesothelioma each year. It affects the lining around the testes, which is called the tunica vaginalis.
Mesothelioma Immunotherapy Facts
When a cancerous tumor of any type develops in our bodies, it is a failure of our immune system. The immune cells that circulate through our blood vessels are powerful disease fighters. Every day, they prevent illness and infection by killing off invading cells.
Cancer cells are trickier than most diseases, however. They have evolved ways to fool our immune system and even shut it down. Immunotherapy drugs seek to reactivate the natural disease-fighting power of our immune system.
How Does Mesothelioma Immunotherapy Work?
Each immunotherapy drug targets a specific part of the immune response cycle. Some expose cancerous cells that were masquerading as normal cells. Others, like tremelimumab mesothelioma immunotherapy, turn on parts of the immune response system that have been turned off by the cancer cells.
Some of the most powerful disease-fighters in your body’s immunity arsenal are T cells. These cells are activated and replicate themselves when they sense a threat. Some cancerous tumors survive by blocking T cells from seeing the danger they pose. When this happens, the number of T cells doesn’t increase, the T cells ignore the malignant cells, and the cancer is able to grow unchecked.
There are different types of immunotherapies because there are different types of cancerous tumors. Even in two people with the same type of mesothelioma, the way the cancer cells get around the immune system may be different.
Before you start mesothelioma immunotherapy, your doctor may want to take a second biopsy or perform more tests on the tissue from your first biopsy. This new testing will find out how the cells in your malignancy operate. This information will help your doctor prescribe the best immunotherapy for you.
What is Mesothelioma Immunotherapy?
Much of the focus of immunotherapy drugs targeted at mesothelioma has been a protein called programmed death-ligand 1 or PD-L1. PD-L1 works to depress your immune response at times when your body needs to hold the immune system in check. The most obvious place where this is important is during pregnancy. Without a mechanism like PD-L1, your body might treat the baby as an invader and attack it.
Programmed cell death protein 1 or PD-1 is the part of the surface of T cells that receives PD-L1. When PD-L1 binds with PD-1, it switches the immune response off. Some cancerous tumors use this mechanism to their advantage. They have extra PD-L1 and send it out to bind with PD-1 and turn T cells off.
You may hear tumors referred to as PD-L1 positive or PD-L1 negative. PD-L1 positive tumors have extra PD-L1 and use this to fool the immune system. Patients with these types of tumors may be more likely to respond to mesothelioma immunotherapy treatments such as Opdivo and Keytruda, that work on the PD-L1 to PD-1 connection.
Although tremelimumab mesothelioma immunotherapy operates on a different protein-receptor combination, it is often combined with an immunotherapy drug that blocks PD-L1 from binding with PD-1. All these treatments are a type of immunotherapy called checkpoint inhibitors or checkpoint blockers, because they prevent certain proteins from turning off your T cells.
Tremelimumab Mesothelioma Immunotherapy
Tremelimumab activates a type of T cell called cytotoxic T lymphocytes or CTLs. The checkpoint that turns off CTLs is a protein on their surface called CTLA-4. Tremelimumab mesothelioma immunotherapy drugs bind to CTLA-4 and prevent the cancer cell ligands B7.1 and B7.2 from shutting them down.
Tremelimumab is a type of monoclonal antibody. This means it binds with one specific protein, so it is very narrowly targeted.
Tremelimumab Mesothelioma Immunotherapy and Orphan Drug Status
Tremelimumab is unusual because some of the first testing has been as a treatment for mesothelioma. While there are clinical trials of other immunotherapies with mesothelioma patients, those drugs were originally approved for treatment of other diseases, including non-small cell lung cancer (NSCLC). Immunotherapies for NSCLC are often helpful to mesothelioma patients as well.
In 2015, after a promising trial on mesothelioma patients in Italy, the US Food & Drug Administration (FDA) granted tremelimumab mesothelioma immunotherapy Orphan Drug Designation. The FDA defines an orphan drug as one that is used to treat a disease that affects fewer than 200,000 people.
Because the market is smaller, it’s not always profitable for drug companies to develop treatments for rare diseases such as mesothelioma. The Orphan Drug Act encourages research on such treatments by providing incentives that make the FDA approval process less expensive.
When tremelimumab received its Orphan Drug Designation, it seemed to hold great hope for mesothelioma patients. Results since that time have been more mixed, but it is still encouraging that drug companies and researchers are recognizing the importance of finding new treatments (and someday a cure) for mesothelioma.
Tremelimumab Mesothelioma Immunotherapy Clinical Trials
After lab testing and development, if a treatment is deemed safe enough to test on humans, researchers will set up clinical trials. Clinical trials usually have at least three phases. Each phase may also have sub-phases.
In a Phase 1 clinical trial, a small number of patients are enrolled. Phase 1 trials are used mainly to determine safe dosages and how much the body can tolerate without dangerous side effects. If the drug appears safe, it moves on to the next phase.
A Phase 2 clinical trial expands the number of participants and looks at both safety and the effectiveness of the treatment.
By the Phase 3 clinical trial, researchers are ready to enroll a large number of participants. Phase 3 allows them to compile better data on the effectiveness of the drug across a broad range of patients.
The very small Phase 2 trial of tremelimumab mesothelioma immunotherapy in Siena, Italy, that we mentioned above, published impressive results in 2015. All the patients in the study had advanced mesothelioma that could not be removed surgically – the worst prognosis for mesothelioma patients. After a year, almost half of the 29 patients in the study were still alive and beating the odds.
The difference between the Siena study and other clinical trials of tremelimumab mesothelioma immunotherapy was that the drug was administered more aggressively. Most patients were able to tolerate the larger dose and this was more effective in controlling their tumors.
A year later, AstraZeneca, the maker of tremelimumab, announced very different results for another mesothelioma clinical trial. This much larger study (571 patients) showed little or no difference between those who received the tremelimumab mesothelioma immunotherapy and those who got a placebo.
Both of these clinical trials studied tremelimumab as a monotherapy. Monotherapy is treatment of one type alone. Mesothelioma doctors have found that most mesothelioma patients respond better when they receive more than one type of treatment or multimodal mesothelioma therapy.
Tremelimumab and Durvalumab
Durvalumab (marketed as Imfinzi) is a PD-L1 blocker immunotherapy drug. In 2016, AstraZeneca announced the results of a Phase 1b clinical trial on patients with advanced NSCLC. The study found that this two-drug combination was more effective than other immunotherapy drugs that had been studied. However, the side effects were significant, so some patients were not able to tolerate the treatment and dropped out.
The 2016 study offered a promising note about the potential of tremelimumab mesothelioma immunotherapy combined with durvalumab. The researchers found that the treatment was almost as effective in patients who were PD-L1 negative as in those who were positive for this immune suppression pathway. This is important because, while there are several promising immune checkpoint inhibitors that operate on PD-L1, not all tumors use this mechanism to turn off the immune system.
Can I Get Tremelimumab Mesothelioma Immunotherapy Treatment?
At this time, tremelimumab is not approved by the FDA. There are, however, continuing clinical trials. Ask your doctor if tremelimumab mesothelioma immunotherapy might be a good choice for you. You can find out about clinical trials in your area through your mesothelioma specialist or at clinicaltrials.gov.
Immunotherapy as Part of Multimodal Mesothelioma Treatment
Neither surgery alone nor chemotherapy alone works as well as the combination of the two. It is considered a standard of care for mesothelioma patients to receive at least two forms of treatment.
Immunotherapy can be an important part of this multimodal approach to mesothelioma care. Treatments such as tremelimumab mesothelioma immunotherapy may work when other types of mesothelioma treatment are no longer keeping the cancer in check.
Second- and Third-Line Mesothelioma Treatment
First-line treatments are the preferred options for treating a disease. For mesothelioma, first-line treatments include surgery and radiation. In addition, almost every mesothelioma patient receives some form of traditional chemotherapy. First-line treatments are the ones that have been proven most effective for most patients.
If you stop responding to a first-line treatment like chemotherapy or if the treatment stops working, your doctor will try a second-line treatment. If that doesn’t work or stops working, you may receive a third-line treatment.
Although there are some researchers studying a protocol where mesothelioma patients receive immunotherapy before surgery, treatments such as tremelimumab mesothelioma immunotherapy are currently considered second-line or third-line treatments. If your tumor stops responding to chemotherapy, immunotherapy may be a good choice for you.
Tremelimumab mesothelioma immunotherapy may also help patients who aren’t eligible for mesothelioma surgery. When mesothelioma is diagnosed after it has progressed to a more advanced stage or if the tumor is in a place where it would be dangerous to operate, immunotherapy can be a last line of defense to stop the progression of the disease.
Tremelimumab Mesothelioma Immunotherapy Side Effects
Because tremelimumab is still in clinical trials, only some of the side effects are known. The most extreme side effects among study participants included digestive disorders such as diarrhea and colitis.
Additional side effects reported include:
- Skin issues such as rashes and vitiligo
- Thyroid problems
- Immune reactions such as Guillain-Barre syndrome (a feeling of sudden and extreme weakness in your muscles)
Reports from the studies are that most side effects were treatable, though some patients did drop out due to adverse side effects.
The combination of tremelimumab with durvalumab or other immunotherapy drugs is also still in clinical trials. This immunotherapy combination may lead to additional side effects.