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Tumors, including mesothelioma and the deadly skin cancer melanoma, use several methods to hide from the immune system. Since mesothelioma and melanoma tumors have similar characteristics, some melanoma treatments are being tested for their efficacy on mesothelioma tumors. Many tumors express proteins that turn off the T cells that would normally kill them. Blocking that “off signal” or “checkpoint signal” is a very promising type of immunotherapy for cancer. It’s like opening the handcuffs on a person’s immune response so their immune system can kill the cancer cells.
Two checkpoint inhibitor compounds have been approved for treatment of advanced melanoma. Some patients live more than 8 years after treatment.1
Two clinical trials of a checkpoint inhibitor in mesothelioma patients have increased overall survival of some patients with mesothelioma.2 A third trial is now recruiting mesothelioma patients.2
What is a checkpoint signal?
The immune system uses T cells to fight and defeat not only infections but also to kill any abnormal cells that are growing too fast—such as tumor cells. After the infection is gone, the surrounding tissues need to be able to calm the fighting spirit of the T cells. T cells have several types of receptors that reduce its fighting ability. These receptors are sometimes called checkpoints.
Two different proteins belong to the checkpoint family of receptors that live on the surface of T cells:
- CTLA-4, which stands for cytotoxic T lymphocyte protein 4, and
- PD-1 which stands for programmed cell death protein 1.
About 50% of the mesothelioma cell lines express the receptors for PD-1.2 Thus, the cells that express the receptors can turn off the T cells when they come to kill the tumor cells.
Checkpoint inhibitors act like the keys that unlock the genetic handcuffs that inhibit T cells from activating and killing tumor cells.
Ipilimumab (Yervoy) was approved for the treatment of malignant melanoma. Clinical trials for the treatment of other types of cancer, such as lung cancer, are ongoing. Ipilimumab prolongs the survival of about 20% of malignant melanoma patients by years.3 Unfortunately, about 10% have severe side effects and can die from the treatment.3
Some patients with both autoimmune disease and melanoma had a flare of their autoimmune disease (multiple sclerosis) after taking the CTLA4 inhibitor.4 A few patients developed an autoimmune disease.5
Tremelimumab, a different anti-CTLA4 inhibitor, is being investigated for treatment for melanoma, lung cancer and mesothelioma. It is the first checkpoint inhibitor to be evaluated in mesothelioma patients.
Two types of inhibitors are being evaluated:
- anti-PD-1 antibody and
- antibody to the receptor of PD-1 called anti-PD-L1 antibody.
The first anti-PD-1 inhibitor, Keytruda (pembrolizumab) has been approved for treatment of melanoma. They have not been tested on mesothelioma yet.
What are the patient’s chances that the treatment will help?
Dr. Calabro says, “A critical and unsettled issue in the course of CTLA4 blockade derives from the lack of reliable predictive biomarkers of response to treatment.”7 So there’s no definitive test that can predict which patients will benefit from the treatment. Scientists are continuing to search for useful markers to understand how to best administer treatment protocols.
Dr. Calabro et al treated 29 mesothelioma patients with the anti-CTLA4 monoclonal antibody, tremelimumab once every 90 days in an open label trial. Two of the mesothelioma patients had partial responses (6.9%) and 7 patients (24.1%) had stable disease. Nine mesothelioma patients lived for more than 18 months, 8 for more than 24 months, and 3 for more than 30 months.7
Although no marker prior to treatment predicted which patients would respond, they monitored the expansion of T cells in the treated patients with various markers. Most patients (10 of 13 patients) experienced longer survival with this treatment if they had a higher number of helper T cells that were ICOS positive on day 30.7
Mesothelioma patients with a healthier status also lived longer with this treatment (median survival 17.1 months).7,8. This treatment did not prolong survival in patients with a poor health status (average survival 5.7 months, range 5.5 to 5.9 months), as measured by EORTC score.7,8
A clinical trial is currently recruiting 564 mesothelioma patients for testing the efficacy and safety of tremelimumab: D4880C00003 (NCT01843374)2
It’s important to discuss the potential risks and potential benefits with your physicians and family before enrolling in any clinical trial.
Lebbe C, Weber JS, Maio M et al. Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Annals of oncology 2014;25(11):2277-2284.
Calabro L, Ceresoli GL, di Pietro A et al. CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy? Cancer Immunol Immunother 2014.
Yuan J, Adamow M, Ginsberg BA et al. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci U S A 2011;108(40):16723-16728.
Gettings EJ, Hackett CT, Scott TF. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler 2014.
Chodakiewitz Y, Brown S, Boxerman JL, Brody JM, Rogg JM. Ipilimumab treatment associated pituitary hypophysitis: clinical presentation and imaging diagnosis. Clin Neurol Neurosurg 2014;125125-130.
Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control 2014;21(3):231-237.
Calabro L, Morra A, Fonsatti E et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. The Lancet. Oncology 2013;14(11):1104-1111.
Fennell DA, Parmar A, Shamash J et al. Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials. J Clin Oncol 2005;23(1):184-189.