Experimental Mesothelioma Immunotherapies
Immunotherapy uses the patient’s own immune system to recognize and fight cancer. In the past, this treatment was considered entirely experimental for mesothelioma. However, a recent approval by the U.S. Food and Drug Administration (FDA) has changed that.
The combination of Opdivo® (nivolumab) and Yervoy® (ipilimumab) gained FDA approval in October 2020. The immunotherapy combination was cleared for first-line treatment of adults with inoperable malignant pleural mesothelioma. In a clinical trial, patients treated with Opdivo and Yervoy had a median survival of 18.1 months. This was about four months better than patients treated with chemotherapy alone.
Opdivo and Yervoy now stand as a clinically available treatment option for mesothelioma patients. However, researchers continue studying other experimental immunotherapies for mesothelioma. Immunotherapies under active investigation for mesothelioma include CAR T cells and checkpoint inhibitors. This research may help expand immunotherapy treatment options for mesothelioma.
CAR T-Cell Therapy
CAR T-cell therapy is a form of immunotherapy that equips immune cells to recognize and attack cancer. At this time, CAR T-cell therapies are considered entirely experimental for mesothelioma.
CAR T-Cell Therapy Procedure Overview
Manufacturing protocols vary, but CAR T-cell treatments generally follow these common steps:
- A doctor collects immune cells called T cells from the patient.
- Scientists reprogram the T cells in a lab, transforming them into CAR T cells. This step gives the T cells the ability to recognize and fight cancer cells.
- A healthcare provider returns the CAR T cells to the patient.
CAR T cells are programmed to recognize a specific aspect of cancer cells. This helps the CAR T cells attack cancer cells instead of healthy cells. For mesothelioma, scientists commonly program CAR T cells to recognize a protein called mesothelin. Mesothelioma cells make a large amount of mesothelin.
This strategy has achieved encouraging results in early testing. In a recent study, pleural mesothelioma patients received CAR T-cell therapy and Keytruda® (pembrolizumab). Keytruda is an immunotherapy drug similar to Opdivo.
Patients treated with this combination achieved a median survival of 23.9 months. In this study, the CAR T-cell/Keytruda therapy constituted a second-line treatment. Patients survived more than a year longer than those in earlier second-line treatment studies.
No CAR T-cell therapies have gained FDA approval for mesothelioma at this time. However, research into CAR T-cell variations is ongoing.
One ongoing clinical trial is evaluating an advanced version of mesothelioma CAR T-cell therapy. The CAR T cells target mesothelin. The CAR T cells also produce a protein that functions like Keytruda. This approach mimics the CAR T-cell/Keytruda therapy above in a single rather than combination treatment.
Both of these CAR T-cell approaches incorporate checkpoint inhibitors. Checkpoint inhibitors are also the subject of active mesothelioma research.
Checkpoint inhibitor drugs interfere with immune checkpoints. These checkpoints safeguard healthy cells, protecting them from attack by the immune system. But cancer cells can also use these checkpoints to dodge attacks from immune cells.
Checkpoint inhibitors interrupt specific checkpoints, allowing immune cells to attack cancer cells. Opdivo and Yervoy are both checkpoint inhibitors, targeting separate checkpoints.
The Opdivo/Yervoy combination is the only checkpoint inhibitor therapy approved for mesothelioma. Keytruda is another checkpoint inhibitor doctors may use for mesothelioma.
Fact: The Opdivo/Yervoy combination is one of the first treatments to achieve comparable success in all common mesothelioma cell types.
Context: Mesothelioma occurs in three main cell types: epithelioid, sarcomatoid and biphasic. Epithelioid mesothelioma generally responds better to conventional treatment than the other types. However, with Opdivo/Yervoy treatment, patients of all cell types achieved comparable survival. Epithelioid patients had a median survival of 18.7 months. Non-epithelioid patients (sarcomatoid and biphasic) had a median survival of 18.1 months.
Other checkpoint inhibitors still fall into the experimental category for mesothelioma. Several of these drugs have achieved promising results in early trials.
- Imfinzi® (durvalumab) and Imjudo® (tremelimumab): Researchers studied this combination in the NIBIT-MESO-1 trial. Mesothelioma patients received multiple rounds of Imfinzi and Imjudo. They had a median survival of about 26 months.
- Tecentriq® (atezolizumab) and chemotherapy: Doctors treated pleural mesothelioma patients with Tecentriq and chemotherapy. The chemotherapy consisted of pemetrexed and cisplatin. Patients went on to surgery and additional treatments if eligible. Preliminary study results indicated median survival will be better than 20 months.
Checkpoint inhibitor research continues through multiple ongoing clinical trials. Future studies will help demonstrate how much these drugs can improve mesothelioma prognosis.
Resources for Mesothelioma Patients
02. Photodynamic Therapy
Experimental Photodynamic Therapy for Mesothelioma
Mesothelioma photodynamic therapy uses light to kill cancer cells. A photosensitizer drug makes tumor cells sensitive to a certain kind of light. This light can then kill the treated cancer cells. This experimental approach may interest researchers due to its relative lack of side effects.
Photodynamic therapy offers a number of advantages, including:
- Can be precisely targeted, unlike many other mesothelioma treatments
- Can be repeated many times at the same site, unlike radiation therapy
- Does not have long-term side effects if used correctly
- May cost less than other treatment options
Studies indicate experimental photodynamic therapy may positively impact mesothelioma life expectancy. One trial demonstrated the effect of photodynamic therapy in the advanced stages of mesothelioma. Pleural mesothelioma patients received photodynamic therapy after surgery. Most study participants went on to chemotherapy treatment as well.
Researchers determined the entire group survived about three years after treatment. However, patients whose cancer had not spread to any lymph nodes lived about seven years.
An upcoming trial will investigate photodynamic therapy in combination with immunotherapy. The IMPALA trial will treat pleural mesothelioma patients who do not respond to conventional treatment. Patients will undergo photodynamic therapy followed by Opdivo (nivolumab).
Researchers estimate the IMPALA trial will conclude in late 2025. By combining photodynamic therapy and immunotherapy, IMPALA will test a multimodal treatment. Many experimental mesothelioma treatments take a similar approach by investigating various multimodal strategies.
03. Multimodal Therapy
Emerging Multimodal Treatments for Mesothelioma
Emerging multimodal mesothelioma treatments combine two or more individual therapies in novel ways. Testing new combinations can help improve this common treatment for pleural and peritoneal mesothelioma.
Researchers hoping to improve multimodal treatment can explore multiple options. They may combine standard treatments in a new way. Researchers may also investigate adding emerging treatments to established protocols.
One routine approach involves administering chemotherapy after mesothelioma surgery. By combining treatments, doctors may be able to remove more mesothelioma cells. This may help prevent recurrence.
Many long-term mesothelioma survivors have undergone similar multimodal treatments. One peritoneal mesothelioma study demonstrated this. Patients in the study received the following treatments:
- Cytoreductive surgery (CRS): A surgery that physically removes as much mesothelioma as possible
- Hyperthermic intraperitoneal chemotherapy (HIPEC): Heated chemotherapy administered throughout the abdomen, immediately following surgery
- Early postoperative intraperitoneal chemotherapy (EPIC): Chemotherapy administered throughout the abdomen within days of surgery
- Normothermic intraperitoneal chemotherapy (NIPEC): Chemotherapy periodically administered within the abdomen over a period of weeks or months
This approach led to a 5-year survival rate of 75%. This means three out of four study patients lived five years or more after treatment.
Several studies have also demonstrated the efficacy of multimodal therapy for pleural mesothelioma.
The SMART Protocol: Multimodal Treatment for Pleural Mesothelioma
The SMART trial treated patients with high-dose radiation prior to surgery. Doctors then removed the cancerous lung and attached tissues through extrapleural pneumonectomy (EPP). EPP occurred within one week of the patient’s last radiation treatment.
Patients with an epithelioid cell type had a median survival of 42.8 months. Despite this success, study authors remain guarded in their enthusiasm for this protocol. The radiation damage opens the door for serious complications. Experts caution against using this protocol outside of advanced centers with substantial surgical experience.
Trimodality Treatment for Pleural Mesothelioma
Another approach currently under investigation combines three separate treatments. Researchers treated pleural mesothelioma patients with chemotherapy, then surgery, then radiation. Patients who completed all three therapies had a median survival of 39 months.
Closer to a Cure: Multimodal Treatment Advances
Multimodal therapies represent an important part of the journey toward a cure for mesothelioma. This combination approach arose after single modality treatments failed to sufficiently prolong survival.
Combination treatments are linked to long-term survival more consistently than single treatment protocols. Further, at least one cancer center has labeled multimodal treatment “the best chance for a cure.”
There is no cure for mesothelioma. Still, multimodal therapies have extended survival long enough to constitute a functional cure for some patients. Multiple studies have reported survival approaching 3.5 years in pleural mesothelioma patients receiving multimodal treatment. In peritoneal mesothelioma, multimodal treatments have extended survival to 15 years or more.
With continued study, researchers may bring multimodal treatments even closer to curing mesothelioma.
04. Tumor Treating Fields
Tumor Treating Fields for Mesothelioma
Tumor Treating Fields (TTFields) represent a relatively new treatment option for mesothelioma patients. TTFields use mild electrical currents to interrupt the growth of cancer cells. This interruption may slow or stop mesothelioma tumor growth.
Patients receive TTField treatment through a portable device called the Optune Lua™. The FDA cleared the Optune Lua for use in patients with inoperable, locally advanced or metastatic pleural mesothelioma. It can be used as a first-line treatment in conjunction with pemetrexed and platinum chemotherapy.
In a clinical trial of Optune Lua-based therapy in pleural mesothelioma:
- 62% of patients lived at least one year.
- 57% of patients saw tumor growth stop.
TTFields were considered an experimental mesothelioma treatment until 2019. At that time, the FDA approved the Optune Lua for use in mesothelioma. Now, hospitals all over the U.S. offer Optune Lua treatment for mesothelioma.
05. Gene Therapy
Gene and Epigenetic Therapies for Mesothelioma
Gene therapy and epigenetic therapy address DNA-related problems that contribute to cancer. These technologies may provide cells with new genes or adjust the way cells use existing genes.
Few gene therapies have successfully moved beyond the experimental stage for any condition. However, research has identified a couple of approaches that may someday benefit mesothelioma patients.
Mesothelioma Gene Therapy
Gene therapy uses new genes (DNA fragments) to address problems caused by missing or damaged DNA. It can also give cells additional DNA, allowing them to make a helpful new protein.
Researchers have investigated gene transfer for mesothelioma. This approach introduces genes to cancer cells. The new genes can help slow tumor growth or kill the cancer cells.
Gene transfer can be accomplished through oncolytic virotherapy. This technology uses an oncolytic virus, which is a virus that kills cancer cells. The virus delivers a gene to cancer cells. This forces the cells to make a protein that kills the cells directly or helps the immune system kill the cells.
Experimental Gene Therapy Study in Mesothelioma
One mesothelioma gene therapy study treated patients with inoperable pleural mesothelioma. The treatment, called Ad.hIFN-α2b, delivered a gene for a protein called interferon-alpha. Interferon-alpha can slow cancer cell growth and help the immune system kill cancer cells.
Treated mesothelioma cells produced interferon-alpha. Patients treated with this gene therapy had a median survival of 13 months. However, patients who received pemetrexed before and after this gene therapy had a median survival of 26 months.
Researchers continue studying experimental gene therapies for mesothelioma. Any patient interested in gene therapy should discuss options with a mesothelioma doctor. The doctor can help the patient find the best treatment for their situation.
Mesothelioma Epigenetic Therapy
Epigenetic therapy treats cancer by changing how cells use the DNA they already have. Epigenetic approaches do not add new DNA to target cells, unlike gene therapy.
Research indicates epigenetic changes play a role in mesothelioma development. These changes may be triggered by exposure to asbestos fibers. Some data indicates certain epigenetic changes may affect survival in pleural mesothelioma.
One preclinical study tested an antibiotic called mithramycin as a potential epigenetic mesothelioma treatment. Data suggests low-dose mithramycin can positively impact epigenetic changes in mesothelioma cells.
Additional studies are necessary before epigenetic therapy can become a treatment option for mesothelioma.
Experimental Cryotherapy for Mesothelioma
Cryotherapy uses extremely cold fluid or gas to destroy cancer cells by freezing them. This treatment can be challenging, as physicians can only treat tumors they can see. However, cryotherapy offers a number of advantages, including:
- Fewer side effects than traditional surgery
- Potential option for patients who do not respond to standard treatment
- Safe to repeat or use alongside other mesothelioma cancer treatments
One study of experimental cryotherapy treated patients with recurrent pleural mesothelioma. Doctors treated 110 mesothelioma tumors during 89 cryotherapy sessions. Three years after treatment, 74% of patients still had zero recurrence.
Experimental Mesothelioma Chemotherapy
Chemotherapy is a type of drug that kills fast-growing cells, including cancer cells. It is the standard treatment for inoperable pleural mesothelioma. In general, mesothelioma chemotherapy includes pemetrexed and cisplatin or carboplatin.
Despite its standard status, chemotherapy has not been associated with the best mesothelioma prognosis. However, researchers are investigating new ways to administer chemotherapy. In early trials, experimental chemotherapy treatments have positively impacted some patients.
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) uses pressure to enhance chemotherapy. The drug is suspended in very small droplets surrounded by gas. A doctor can release this pressurized, chemotherapy-containing gas, spraying it on tumor tissue.
Research indicates this approach increases the amount of chemotherapy drug in tumor tissue. However, it does not increase chemotherapy levels in the bloodstream. This may mean PIPAC patients will experience fewer side effects than with systemic treatment.
Experimental PIPAC Study
One study investigated PIPAC in 26 mesothelioma patients. All study patients had a diagnosis of inoperable peritoneal mesothelioma. Patients received PIPAC treatment and systemic chemotherapy.
The most successful mesothelioma treatments generally include some form of surgery. Therefore, a treatment that allows an inoperable patient to become eligible for surgery is an exciting development.
After treatment, 58% of patients became eligible for cytoreductive surgery and HIPEC. Patients who became eligible for surgery had a median progression-free survival of 33.5 months. This means they lived nearly three years after treatment with no evidence of cancer growth.
PIPAC research for mesothelioma is ongoing in the form of the MESOTIP clinical trial.
Sticky Chemotherapy or Chemotherapy Glue
One unique approach to improving chemotherapy involves making it sticky. Individuals might think of this technology as chemotherapy glue. Researchers combined a natural glue called fibrin with chemotherapy. Fibrin is the biological glue responsible for forming scabs.
This combination allows doctors to apply a chemotherapy-containing glue to tumors. Although it may sound odd, this approach offers distinct advantages:
- Allows oncologists to apply a high concentration of chemotherapy directly to tumors
- May not expose the rest of the patient’s body to the concentrated chemotherapy
- May substantially prolong treatment time by physically adhering chemotherapy to tumors
An early study of this technology in gastric cancer patients reported encouraging results. Chemotherapy glue patients survived about seven months longer than those treated with HIPEC.
Researchers have also investigated chemotherapy glue in pleural mesothelioma. Patients received cisplatin-containing fibrin glue after surgery. Doctors applied the glue to the edges of surgically removed tissue. This is where microscopic tumor cells could be left behind.
The study reported a median time to recurrence of eight months. Patients also had a median survival of 21 months. According to researchers, further investigation of fibrin-cisplatin chemotherapy glue for pleural mesothelioma is ongoing.
08. Other Emerging Treatments
Targeted Drugs and Other Experimental Mesothelioma Therapies
Targeted therapies identify and attack specific types of cancer cells, such as mesothelioma cells. Targeted drugs may use a variety of approaches to injure and kill cancer cells without hurting healthy cells. Several studies have investigated targeted drugs for mesothelioma.
Researchers are also investigating mesothelioma treatments that do not fit into any existing categories.
Targeted Therapies for Mesothelioma
What it is: Hiltonol is a synthetic molecule that contains instructions for a helpful protein. The protein is called interferon-gamma. Immune cells that produce interferon-gamma may be able to kill cancer cells.
Results so far: Eight patients with solid cancers were treated with hiltonol. One patient achieved stable disease and lived at least six months without progression.
What it is: Pevonedistat interferes with the NAE enzyme. This means NAE cannot function in cells treated with pevonedistat. Without NAE, waste products collect in cancer cells, causing them to slow or stop dividing.
Results so far: Patients with acute myeloid leukemia (AML) received pevonedistat-inclusive treatment. The 1-year survival rate was 45%.
What it is: Olaparib (Lynparza®) interferes with an enzyme called PARP. Cells need PARP to repair DNA damage. Cells treated with olaparib sustain irreparable DNA, causing the cells to die.
Results so far: Olaparib has not yet been tested in individuals diagnosed with mesothelioma. Research indicates it may be effective in as many as ⅔ of mesothelioma patients.
What it is: Talazoparib interferes with an enzyme called PARP. Cells need PARP to repair DNA damage. Cells treated with talazoparib sustain irreparable DNA, causing the cells to die.
Results so far: Talazoparib has not yet been studied in people diagnosed with mesothelioma. However, research indicates mesothelioma cells may be susceptible to talazoparib.
Hybrid Therapies for Mesothelioma
Hybrid mesothelioma therapies combine two treatment approaches in a single drug or substance. Experimental hybrid therapies are exploring multiple combinations.
- Anetumab ravtansine: This therapy is a cancer-fighting drug (ravtansine) physically attached to an antibody. Ravtansine interferes with cell division, which can kill cancer cells. It is attached to an antibody that recognizes mesothelin, a protein commonly made by mesothelioma cells. These properties allow anetumab ravtansine to identify and kill mesothelioma cells.
- Brentuximab vedotin: This therapy is a chemotherapy drug, monomethyl auristatin E (MMAE), attached to an antibody. The antibody portion of this therapy targets a protein called CD30. This protein is made by some forms of mesothelioma. These properties empower brentuximab vedotin to identify and kill mesothelioma cells.
BAY2287411 is an antibody attached to a radioactive molecule. The antibody targets mesothelin, allowing it to identify mesothelioma cells. The radioactive molecule can deliver targeted radiation to cells identified by the antibody.
09. Accessing Treatment
How to Get Treated With Experimental Mesothelioma Therapies
Mesothelioma patients interested in experimental therapies should discuss the options with a mesothelioma expert. If the patient moves forward with experimental treatment, they can take one of three routes:
- Clinical trials: Many patients access experimental treatments through clinical trials. The process requires strict oversight from the FDA and a review board. Trial participants receive full information and proactive monitoring.
- Expanded access (compassionate use): This route allows patients to access experimental therapies outside of a clinical trial. To qualify, patients must have a life-threatening illness with no available standard treatment. Patients must also be ineligible for a clinical trial. This route may not be an option for mesothelioma, as it does have recommended standard treatments.
- Right to try: This route allows patients to access experimental therapies outside of a clinical trial. However, it is not closely monitored by the FDA. Patients and treatments must meet several criteria to pursue this access route.
Patients interested in clinical trials must meet trial eligibility criteria to participate. Eligibility requirements may vary widely. Any interested patient should discuss the options with a mesothelioma doctor. The doctor can help the patient understand the potential risks and benefits of each option.
How Do Treatments Go From Experimental to FDA Approved?
The FDA must evaluate the safety, efficacy and risks of any new drug before it can be approved. Within this process, regulators review preclinical and clinical study information. This helps them determine if the drug’s benefits outweigh its risks for the intended patients.
Clinical trial data figures heavily in this decision. When experimental treatment studies report positive results and safety, the treatment may gain approval. This happened recently with Opdivo (nivolumab) and Yervoy (ipilimumab).
10. Common Questions
Common Questions About Experimental Mesothelioma Treatments
What is the latest treatment for malignant mesothelioma?
- The combination of Opdivo (nivolumab) and Yervoy (ipilimumab) gained FDA approval in October 2020. It is approved for first-line treatment of inoperable pleural mesothelioma. Patients lived about 18.1 months with this treatment.
Can mesothelioma go into remission?
- Some mesothelioma patients have experienced long-term survival after aggressive treatment. Some may consider this as remission. Mesothelioma prognosis depends on several factors including stage at diagnosis, treatment approach and patient health.
What is the latest experimental surgery for mesothelioma?
- Two common pleural mesothelioma surgeries may be considered experimental:
- Pleurectomy/decortication (P/D): A surgery that removes the lining outside the lung and other cancerous tissues, but preserves the lung
- Extrapleural pneumonectomy (EPP): A surgery that removes the lining outside the lung, other cancerous tissues and the affected lung
Researchers have debated the merits of these surgeries for years. Several studies have contributed to this debate. However, recent information indicates P/D may be the better option due to its superior safety profile.