What Is Mesothelioma Immunotherapy?
Immunotherapy is an experimental treatment for mesothelioma. It is not yet a part of standard, first-line treatment for the cancer, but medical research is getting closer to making it a reality.
Certain immunotherapy drugs, such as Keytruda, have helped some people live for years with mesothelioma.
Keytruda is available to mesothelioma patients through clinical trials and compassionate use programs. It is also FDA approved for any cancer that has a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor.
Immunotherapy can enhance the immune system response to mesothelioma cancer, but it has not been able to cure the cancer. Research is integrating immunotherapy as part of a multimodal treatment plan to better manage mesothelioma like a chronic disease.
What Immunotherapies Work Against Mesothelioma?
Several immunotherapy agents, including Keytruda, Opdivo and Yervoy, are now commercially available, and they have shown promising anticancer activity against mesothelioma in recent clinical trials.
Keytruda is an immunotherapy drug used to treat lung cancer, and it’s under investigation to treat mesothelioma. Trials show Keytruda is effective against mesothelioma in certain patients and helps them live longer when the cancer recurs after first-line treatment. One mesothelioma survivor says surgery and Keytruda saved his life, and another survivor says chemotherapy, Keytruda and surgery saved her life.
Opdivo and Yervoy help people live longer after mesothelioma recurs, meaning these drugs might prove more effective as a second-line treatment than chemotherapy. Less than one-third of mesothelioma patients live longer than three months after mesothelioma recurs, but a French clinical trial reported that half of their participants lived longer than three months with the combined treatment of Opdivo and Yervoy.
Benefits of Immunotherapy
Immunotherapy is the hottest topic in cancer research and is widely considered the future of cancer treatment. Aside from the ultimate benefit of potentially keeping cancer in control, the benefits of immunotherapy include:
It harnesses the natural processes of your immune system to fight cancer internally.
Immunotherapy takes a targeted approach that kills only cancer cells, whereas chemotherapy also kills healthy cells.
The side effects of immunotherapy are fewer and often more manageable compared to other anticancer therapies.
Types of Immunotherapy for Mesothelioma
Different types of immunotherapy have been tested on mesothelioma since the 1970s. Recent breakthroughs in research, such as the development of Keytruda and other immune checkpoint inhibitors, made immunotherapy a more viable treatment option for mesothelioma.
Immune Checkpoint Inhibitors
Immune checkpoint inhibitors are drugs that stop cancer cells from hiding from the immune system. Checkpoint inhibitors are made of antibodies that unmask cancer cells and allow the immune system to recognize them and attack. Checkpoint inhibitors for mesothelioma target checkpoints such as CTLA-4, PD-1 and PD-L1.
The most promising checkpoint inhibitors in mesothelioma research currently include Keytruda, Opdivo, Yervoy and Imfinzi (Durvalumab). Another checkpoint inhibitor called SS1P controlled mesothelioma tumors in certain patients but not enough to warrant further study.
Research is underway in Hawaii to develop a preventative mesothelioma vaccine.
Clinical trials have studied some therapeutic vaccines for mesothelioma, and two vaccines in particular, the listeria-based cancer vaccine CRS-207 and galinpepimut-S (WT1), have shown the most promise.
A 2016 study showed that the combination of chemotherapy and CRS-207 controlled tumor growth longer than chemotherapy alone.
In December 2017, a phase II clinical trial designed to test the effectiveness and safety of CRS-207 in combination with Keytruda ended abruptly. Aduro Biotech, the pharmaceutical giant behind the multicenter trial, cited unfavorable results and financial concerns for ending the study.
A phase II clinical trial of the WT1 vaccine reported significantly longer survival and better tumor control among participants who received the vaccine versus those receiving a placebo.
In September 2016, the FDA awarded Fast Track designation to the WT1 vaccine, moving it closer to becoming the first approved second-line treatment for malignant pleural mesothelioma. A phase III trial is planned, pending funding availability.
Monoclonal antibody therapy (mAb) is the most commonly used form of cancer immunotherapy, but it’s not necessarily the most common immunotherapy for mesothelioma. It is considered a targeted therapy because it is focused on a single site within the cancer cell, either an antigen on the surface of the cell or an enzyme or protein within the cell.
Tremelimumab is both a monoclonal antibody and an immune checkpoint inhibitor under investigation for mesothelioma. Clinical trials are testing the drug on mesothelioma patients with mixed results. Some patients respond well, while others show little to no response.
Amatuximab (known as MORAb-009) is a monoclonal antibody that made it to a phase II clinical trial on mesothelioma patients. Not enough patients responded to the therapy to warrant a phase III trial. Overall survival was 14.8 months, and the average survival for mesothelioma is around one year.
One mesothelioma patient, Andy A., responded abnormally well to Amatuximab during a clinical trial. Andy was allowed to stay on the drug for years after the study technically ended because it continued to keep his mesothelioma in control. When the drug suddenly stopped working, Andy turned to complementary therapies including cannabis oil.
Other types of immunotherapy studied on mesothelioma include adoptive cell transfer, cytokines and Bacillus Calmette-Guerin.
Antigens are compounds on the surface of diseased cells and foreign pathogens, such as viruses, that stimulate an immune system response.
Antibodies are proteins made by B cells that identify and attack antigens.
Cytokines are proteins made by T cells that coordinate immune responses against cancer and foreign pathogens.
Adoptive Cell Transfer
Transferring live, whole immune cells into patients is a practice that researchers use on patients with advanced metastatic melanoma or renal cell carcinoma. Adoptive cell transfer is also being investigated for use in patients with mesothelioma.
Injection of dendritic cells following chemotherapy has been tested in a phase I clinical trial. Ten patients previously treated with cisplatin and pemetrexed tolerated the therapy well, and an immune response was documented in the study’s participants.
Another type of adoptive cell transfer being tested in mesothelioma clinical trials is CAR T-cell therapy. This therapy modifies a patient’s own T cells to help the immune system kill cancer cells.
Cytokines, such as tumor necrosis factor, interferon and interleukin-2, are used in immunotherapy to kill cancer cells or stop the birth of new cells. They interact directly with the tumor cells and are given individually or in combination to take advantage of the effect of all of them working together, which is more effective than what each can do individually.
Examples of using cytokines to boost the immune response include:
Interleukin-2 to stimulate the creation of T-cell and natural killer (NK) cells.
Interferon to make antigen-presenting cells (such as dendritic cells) more effective and increase the production of immune molecules like MHC, which help T-cells recognize antigens.
- B cells make antibodies that attack antigens.
- T cells make cytokines and attack damaged or diseased cells.
- Natural killer cells detect and destroy damaged cells.
- Dendritic cells carry antigens to T cells and B cells to initiate an immune response.
- Macrophage cells can swallow and digest worn-out cells and debris.
During the 1970s, researchers discovered that administering weakened forms of a mycobacterial strain called bacillus Calmette-Guerin (BCG) was effective in treating cancer. BCG is made from a live strain of tuberculosis virus found in oxen and cows.
BCG is approved for treating bladder cancer and as a vaccine for tuberculosis. In the 1970s and ’80s, studies were conducted on its usefulness as a treatment for mesothelioma and pleural effusions. In one study, BCG was injected into mesothelioma patients and repeated monthly. The injections prevented reaccumulation of fluid in the lung cavity.
Another study involved 30 patients with various stages of malignant pleural mesothelioma. Patients first underwent a thoracotomy, in which as much of the cancerous tissue as possible was removed. Following chemotherapy or radiation, BCG injections were administered every three weeks. After six weeks, the treatment interval was lengthened to four, five and then six weeks.
Twenty-eight out of 30 patients continued to receive injections, and they reported the injections made them feel much better and their pain was significantly reduced. The researchers noted the best prognosis was achieved when BCG was used in patients with a relatively light tumor load who had undergone thoracotomy. These patients survived an average of 21.5 months, and one patient was still living six years after treatment.
While BCG showed early promise decades ago, it is not currently being offered as a treatment for mesothelioma. However, current immunotherapy studies have been conducted with other forms of mycobacterium, including SRL 172, which failed to find it effective against mesothelioma and non-small cell lung cancer.
How Does Immunotherapy Work?
A basic understanding of the immune system helps people understand how immunotherapy works. The immune system has evolved to protect the body from foreign pathogens — such as viruses and bacteria — and disease development. It also removes damaged or dead cells. Your immune system recognizes internal and external causes of illness, including cancerous cells.
At birth, your immune system is preloaded with all sorts of information to protect you in the world. Your immune system develops as you grow, and it learns to recognize foreign pathogens.
Active Versus Passive Immunotherapy
Immunotherapy drugs are classified as active or passive.
Active immunotherapy induces a durable change in the immune system or an immune system “memory.” This teaches the immune system how to recognize the tumor permanently. Even after the treatment, the immune system remembers to see the cancer cells as foreign and attack them, often because the person has generated their own antibodies against the cancer.
Passive immunotherapy has no lasting immunologic memory. Once you stop treatment, the effect goes away. There is a temporary response, such as when the person’s immune response is activated by the presence of external antibodies.
An example of passive immunotherapy are the monoclonal antibodies that make up checkpoint inhibitors such as Keytruda and Opdivo. Once those antibodies disappear, the immune system doesn’t retain the activity it had when they were present.
- Cancer Vaccines
- CAR-T Cell Therapy
- Immune Checkpoint Inhibitors
Future of Immunotherapy for Mesothelioma
Immunotherapy will likely become an effective treatment option for mesothelioma in the future, especially when combined with other cancer therapies. Some studies have combined immunotherapy with chemotherapy or surgery, and recent results indicate a significant survival benefit in certain patients.
Researchers have discovered a direct correlation between penetrating lymphocytes and mesothelioma prognosis, indicating that enhanced immune response may improve patient outcome. Additionally, laboratory studies of asbestos suggest the mineral compromises immune cells, which could contribute to its carcinogenic effect. Preventative cancer vaccines for people exposed to asbestos could offer chemopreventative benefit in the future, but identifying who could biologically benefit from such therapy is currently challenging.
The exciting news is that immunotherapy is available to people with mesothelioma through clinical trials and compassionate use programs. Some drugs such as Keytruda may be available outside of these programs if a patient shows specific biomarkers.
If your oncologist hasn’t brought up the prospect of immunotherapy, be sure to bring it up and ask if there are any clinical trials near you.
Dr. Dan Sterman Director of pulmonary medicine at New York University
“I believe immunotherapy will become the fourth pillar of treatment for mesothelioma [joining surgery, radiation and chemotherapy]. It could help turn mesothelioma into a chronic disease that people can live with for a long time.”
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Last Modified April 2, 2019