Malignant pleural mesothelioma (MPM) is a type of cancer that originates in the lining of the lungs, and it is caused primarily by exposure to asbestos. Unfortunately, MPM is a highly aggressive and treatment-resistant cancer, and the prognosis for patients with MPM is generally poor. In recent years, there has been growing interest in the use of immunotherapy as a potential treatment option for MPM. Immunotherapy is a type of cancer treatment that works by stimulating the immune system to attack cancer cells.
There are several different types of immunotherapy that have been studied in the context of MPM, including immune checkpoint inhibitors, vaccines, and adoptive cell therapy. In this article, we will review the current state of knowledge regarding the use of immunotherapy in the treatment of MPM.
Immune checkpoint inhibitors
Immune checkpoint inhibitors are a type of immunotherapy that work by blocking proteins on the surface of cancer cells that prevent the immune system from attacking them. Two immune checkpoint inhibitors that have been studied in the context of MPM are pembrolizumab and nivolumab.
Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor on T cells. PD-1 is an immune checkpoint that is upregulated in many types of cancer, including MPM. By blocking PD-1, pembrolizumab can enhance the ability of the immune system to recognize and attack cancer cells.
Several clinical trials have evaluated the use of pembrolizumab in patients with MPM. The KEYNOTE-028 trial enrolled 25 patients with PD-L1-positive MPM (PD-L1 is a protein that is expressed on the surface of some cancer cells and can be used as a biomarker to predict response to immunotherapy). In this trial, pembrolizumab demonstrated a response rate of 20%, with a disease control rate (defined as stable disease, partial response, or complete response) of 44%. The median progression-free survival (PFS) was 6.2 months, and the median overall survival (OS) was 18.5 months.
The KEYNOTE-158 trial enrolled 55 patients with MPM who had received at least one prior line of therapy. In this trial, pembrolizumab demonstrated a response rate of 14%, with a disease control rate of 44%. The median PFS was 2.5 months, and the median OS was 10.7 months.
Based on the results of these trials, pembrolizumab was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of PD-L1-positive MPM in 2020.
Nivolumab is another immune checkpoint inhibitor that targets the PD-1 receptor. Several clinical trials have evaluated the use of nivolumab in patients with MPM. The CheckMate-743 trial enrolled 605 patients with previously untreated MPM and randomized them to receive either nivolumab plus ipilimumab (a type of immune checkpoint inhibitor that targets the CTLA-4 receptor) or chemotherapy with cisplatin and pemetrexed. The trial demonstrated a significant improvement in OS with nivolumab plus ipilimumab compared to chemotherapy, with a median OS of 18.1 months versus 14.1 months. The response rate was 40% with nivolumab plus ipilimumab and 43% with chemotherapy.
Based on the results of this trial, nivolumab plus ipilimumab was granted accelerated approval by the FDA for the first-line treatment of unresectable MPM in 2020.
Vaccines are another type of immunotherapy that have been studied in the context of MPM. Vaccines work by stimulating the immune system to recognize and attack cancer cells by presenting them with antigens (molecules that are specific to cancer cells). Two types of vaccines that have been studied in MPM are dendritic cell vaccines and mesothelin vaccines.
Dendritic cell vaccines
Dendritic cells are a type of immune cell that can stimulate T cells to attack cancer cells. Dendritic cell vaccines work by taking dendritic cells from a patient’s blood, exposing them to mesothelin (a protein that is overexpressed in MPM cells), and then injecting the dendritic cells back into the patient. The hope is that the dendritic cells will present mesothelin to T cells and stimulate an immune response against MPM cells.
Several clinical trials have evaluated the use of dendritic cell vaccines in patients with MPM. The results of these trials have been mixed, with some trials showing a modest improvement in survival and others showing no benefit.
Mesothelin is a protein that is overexpressed in MPM cells and can be used as a target for immunotherapy. Several mesothelin vaccines have been developed, including CRS-207, CRS-207/GVAX, and SS1P. CRS-207 is a live-attenuated Listeria monocytogenes bacteria that has been engineered to express mesothelin. CRS-207/ GVAX is a combination of CRS-207 and a vaccine that targets a protein called granulocyte-macrophage colony-stimulating factor (GM-CSF), which is involved in the production of dendritic cells. SS1P is a recombinant immunotoxin that targets mesothelin and delivers a toxic payload to MPM cells.
Several clinical trials have evaluated the use of mesothelin vaccines in patients with MPM. The results of these trials have been mixed, with some trials showing a modest improvement in survival and others showing no benefit. In general, mesothelin vaccines have been found to be well-tolerated, with few serious adverse events reported.
Adoptive cell therapy
Adoptive cell therapy is a type of immunotherapy that involves collecting T cells from a patient’s blood, genetically engineering them to express a chimeric antigen receptor (CAR) that targets a specific antigen on cancer cells, and then infusing the CAR T cells back into the patient. CAR T cell therapy has been successful in treating some types of blood cancers, but its use in solid tumors like MPM is still in the early stages of development.
Several clinical trials have evaluated the use of CAR T cell therapy in patients with MPM. The results of these trials have been mixed, with some trials showing a modest improvement in survival and others showing no benefit. One challenge with CAR T cell therapy in MPM is identifying a specific antigen that is expressed on MPM cells but not on healthy cells, which can be targeted by the CAR T cells.
In conclusion, immunotherapy has shown promise as a potential treatment option for MPM. Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, have demonstrated efficacy in clinical trials and have been approved for use in certain patients with MPM. Vaccines and adoptive cell therapy are still in the early stages of development and require further study to determine their efficacy in MPM. While immunotherapy has the potential to improve outcomes for patients with MPM, it is important to recognize that not all patients will respond to immunotherapy, and further research is needed to identify biomarkers that can predict response to immunotherapy and to develop more effective treatment strategies for this aggressive cancer.