Dr. James Stevenson, M.D.
Types of Immunotherapy
There are many types of immunotherapy that are being tested to treat mesothelioma and other kinds of cancer. Immunotherapy treatment can be broken up into two broad categories based on how the treatment influences a patient’s immune system. Active immunotherapy evokes a lasting response within the immune system through use of immune memory. It works by stimulating the immune system to act against the cancer cells.
Passive immunotherapy produces the desired cellular reaction by introducing synthetic immune proteins into a patient’s body to help fight cancer. Because the reaction is caused by the introduction of these cells and immune memory is not triggered, the immune response is temporary. Repeated doses of passive immunotherapy treatments may be required.
There are four main types of immunotherapy which fall under the active or passive category:
- Adoptive cell transfer
- Cancer vaccines
- Immune checkpoint inhibitors
- Monoclonal antibodies
Each type of immunotherapy comes with its own possible side effects and benefits.
Adoptive Cell Transfer
Adoptive cell transfer (ACT) treats cancers, like mesothelioma, by enhancing a patient’s T-cells (white blood cells that help trigger an immune response), which can then attack the cancer. This is achieved by removing T-cells from a patient’s tumor and growing large quantities of the cells most active against the cancer in a lab. The process takes 2 – 8 weeks to complete. Once the cells are replicated, they are reintroduced to the patient via injection into a vein. Patients may receive other standard treatments, like chemotherapy and radiation in the interim between when T-cells are extracted and reintroduced.
There are several types of ACT, but the most promising method, and the option that has advanced furthest in trials, is CAR T-cell therapy. The therapy has shown early promising results in malignant pleural mesothelioma patients. An ongoing clinical trial at Memorial Sloan Kettering Cancer Center is treating 10 pleural mesothelioma patients with the therapy. So far, researchers have seen no toxicity among patients and there is evidence of anti-tumor activity. Side effects related to CAR T-cell therapy are generally mild and are easily controlled with medication, or may resolve on their own with no treatment necessary.
Possible Side Effects of CAR T-Cell Therapy
- Accelerated heart rate
- Low blood pressure
- Shortness of breath
Cancer vaccines harness cancer cells or antigens to elicit an immune response in cancer patients. The vaccines are a form of active immunotherapy and are given with the hope that the body will continue to attack the cancer long after vaccination due to immune cell memory.
This immunotherapy modality has shown promise in treating pleural mesothelioma patients. A small clinical trial using a dendritic cell vaccination and chemotherapy found that patients’ life expectancies were extended dramatically. Seven patients in the study achieved survival of 24 months or longer, with two patients surviving at least 50 and 66 months, which is more than triple the average pleural mesothelioma survival time of 12 months.
Side effects related to cancer vaccines vary based on the cancer being treated, and if whole cancer cells or antigens are being used within the vaccine. In the dendritic cell trial, patients experienced only a mild fever after vaccination.
Immune Checkpoint Inhibitors
Checkpoint inhibitors treat cancer by preventing cancer cells from evading the immune system. Cancer cells often mimic the checkpoints found in healthy cells, which causes the immune system to not categorize them as a foreign danger within the body. Checkpoint inhibitors commonly target either the PD-1 checkpoint and PD-L1 protein found in T-cells, or the CTLA-4 protein, also in T-cells. The two most common PD-1 checkpoint inhibitors are Keytruda® and Opdivo.
Currently, immune checkpoint inhibitors are FDA approved for the treatment of multiple cancers, including bladder cancer, non-small cell and small cell lung cancers and melanoma. Studies have shown similarities between melanoma and mesothelioma in the past, which caused researchers to be hopeful about the possibility of using checkpoint inhibitors for mesothelioma cancer treatment. Ongoing clinical trials are actively testing different immune checkpoint inhibitors for mesothelioma, with some completed trials showing promising results in improving tumor response rates and extending survival when used alone or with other therapies. Though not yet FDA approved for mesothelioma, the National Comprehensive Cancer Network (NCCN) has added a recommendation that Keytruda® and Opdivo (used alone or in combination with another immunotherapy drug called Yervoy) be considered as subsequent treatment options for pleural mesothelioma patients who have already received some form of front-line chemotherapy. This represents a significant advance in treatment options available for mesothelioma patients.
Common side effects related to checkpoint inhibitors are mild. However, there are rare instances of more serious issues, including problems within the organs such as the lungs, intestines or liver.
Possible Side Effects of Checkpoint Inhibitors
- Loss of appetite
- Skin rash
Monoclonal antibodies (mAbs) are lab-produced immune system proteins. These proteins are engineered to attach to antigens found on mesothelioma cells, making it easier for the immune system to identify the cancer cells and trigger a response. Immunotherapy treatment using monoclonal antibodies is passive in nature.
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So far, the U.S. Food and Drug Administration has only approved two monoclonal antibodies, ramucirumab (Cyramza) and bevacizumab (Avastin). Neither have been approved for treatment of mesothelioma, but have shown promising results in clinical trials. A phase III trial has shown that when bevacizumab, which impedes blood vessel growth, is combined with chemotherapy, pleural mesothelioma patient survival is extended. Researchers found an overall median survival of 18.8 months for 223 patients treated with a combination of chemotherapy drugs (cisplatin and pemetrexed) and bevacizumab. Patients in the trial who were treated with chemotherapy alone had a median overall survival of 16.1 months. Typically, pleural mesothelioma patients survive for just six months to one year following diagnosis.
Side effects of bevacizumab and other monoclonal antibodies are typically mild, but patients should discuss the benefits and risks, such as toxicity, with their healthcare team prior to making any treatment decisions.
Possible Side Effects of Monoclonal Antibodies
- Low blood pressure
Based on the success of monoclonal antibodies, like bevacizumab, in clinical trials, some doctors believe that the immunotherapy drug should be considered as a first-line treatment option for mesothelioma patients who are ineligible for surgery. Though not yet FDA approved for mesothelioma, the National Comprehensive Cancer Network (NCCN) has added a combination of pemetrexed, cisplatin and bevacizumab as a recommended first-line treatment for unresectable mesothelioma.
Resources for Mesothelioma Patients
Eligibility for Mesothelioma Immunotherapy
In general, most mesothelioma patients can be candidates for immunotherapy, given as a standard therapy or through participation in clinical trials. Patients with certain types of pre-existing immune conditions may not be eligible for immunotherapy. Each clinical trial has unique eligibility criteria, which can include things like type of mesothelioma, cell type, stage and patient age. If interested in receiving immunotherapy or participating in a clinical trial, patients should discuss potential benefits and risks with their medical team.
Immunotherapy is a growing field of cancer research and therapy, not just for mesothelioma. As cancer research progresses, more clinical trials for the emerging treatment will likely become available. Researchers hope to continue to improve the efficacy of the treatment and eventually achieve FDA approval and/or inclusion in nationally recognized treatment guidelines, allowing the treatment to be widely available to more patients.