Dendritic Cell Therapy for Pleural Mesothelioma (Cancer of the Lung Lining)

Our lungs are covered by the  pleura , a two-layered membrane (see the image below). A small amount of fluid between the pleural layers is produced by mesothelial cells.

Tissues similar to the lung lining also occur elsewhere in the body. They are called the peritoneum around the abdomen and the pericardium around the heart. Malignant mesothelioma is cancer originating in these membranes.

Of patients with malignant mesothelioma, 80% have pleural malignant mesothelioma.

An Overview of Mesothelioma

The main cause of malignant mesothelioma is asbestos exposure. Less common causes include genetic factors and a virus called Simian 40.

Pleural mesothelioma symptoms include shortness of breath, chest pain and cough. It can be difficult to diagnose pleural mesothelioma early, and the disease is usually diagnosed at an advanced stage.

Mesothelioma is a rare cancer. In countries with occupational asbestos exposure, it is more common in men; with environmental asbestos exposure, as in Turkey, rates are similar in women and men.

Worldwide incidence is 1-2 per 1 million people, while approximately 500 new cases of mesothelioma are diagnosed annually in Turkey.

Asbestos is a group of naturally occurring minerals widely used in the past in industries such as construction, shipbuilding and automotive manufacturing. Its use has been banned or restricted in many countries because of its harmful health effects, particularly cancers such as pleural mesothelioma. Turkey completely banned asbestos use in 2010.

Some areas of Turkey with substantial environmental asbestos exposure are shown below:

People living in these areas are at high risk because of environmental asbestos exposure. When inhaled, asbestos fibers can accumulate in the lungs and cause various health problems over many years.

Current Advances in Pleural Mesothelioma Treatment

In 2020, nivolumab (Opdivo) plus ipilimumab (Yervoy), a combination of two  immunotherapy drugs, received FDA approval for unresectable pleural  mesothelioma  in adults as  first-line treatment. This was the first FDA immunotherapy approval for mesothelioma, providing, regardless of subtype,  an approved chemotherapy-free treatment  option. With this approval, there are 3 FDA-approved treatments  for pleural mesothelioma: " cisplatin + pemetrexed" chemotherapy; adding electric field therapy (the NovoTTF-100L System) to that chemotherapy; and nivolumab–ipilimumab. We also know that adding  bevacizumab  (Altuzan, Avastin, Mvasi), an  antiangiogenic  drug that inhibits new blood vessel formation, substantially improves survival rates. This was shown in the phase-III trial reported in 2015,  MAPS, and in clinical practice in Turkey we seek off-label approval to add it to treatment.

Below is  an indirect comparison of FDA-approved treatments for pleural mesothelioma :

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A New Treatment for Pleural Mesothelioma: Dendritic Cell Therapy

Dendritic cell therapy is a form of immunotherapy intended to activate the patient's immune system against cancer. It aims to enable the patient's dendritic cells—part of the immune system—to interact with tumor cells, recognize them and attack them. Dendritic cells are loaded with tumor antigens and then returned to the patient to strengthen the immune response.

FDA-Approved Dendritic Cell Therapies

Several dendritic cell therapies are currently approved by the FDA:

1. Sipuleucel-T (Provenge): approved for metastatic castration-resistant prostate cancer, this treatment involves processing the patient's own dendritic cells with tumor antigens in a laboratory and then returning them to the patient.

Dendritic cell therapies are an innovative approach to cancer treatment, with research progressing rapidly. However, their effectiveness and applications in each cancer type are still being investigated.

Dendritic Cell Therapy and Pleural Mesothelioma

Dendritic cell therapy is a promising research area for challenging cancers such as pleural mesothelioma. On 4 June 2024, Aerts and colleagues published in The Lancet Oncology their phase II/III DENIM trial, examining whether dendritic cells loaded with allogeneic tumor cell lysate (called MesoPher) could improve overall survival in pleural mesothelioma. The trial found no overall survival benefit. However, future combination treatments are thought to have the potential to improve the effectiveness of this approach.

Trial Details

In this open-label trial, 176 patients from four centers in Belgium, France and the Netherlands were randomized between June 2018 and June 2021 to MesoPher plus best supportive care (88 patients) or best supportive care alone (88 patients).

MesoPher treatment comprised up to five infusions of 25 × 10^6 dendritic cells on days 1, 15 and 29 and at weeks 18 and 30. Patients had nonprogressing disease after four to six cycles of standard pemetrexed plus cisplatin or carboplatin chemotherapy.

The primary endpoint was overall survival.

Overall Survival

At the June 2023 data cutoff, after a median follow-up of 15.1 months (interquartile range = 9.5–22.4 months),

• Overall Survival (Months): 16.8 months in the MesoPher group, versus 18.3 months in the supportive-care group.
• Progression-Free Survival (Months): 5.4 months in the MesoPher group, versus 3.2 months in the supportive-care group.
• 12-Month Survival Rate: 62% in the MesoPher group, versus 67% in the supportive-care group.
• 24-Month Survival Rate: 43% in the MesoPher group, versus 51% in the supportive-care group.

Subsequently, 60% of patients in the MesoPher/best supportive-care group and 58% in the best supportive-care-only group received immune checkpoint inhibitor therapy, such as anti-PD-1 antibodies.

Side Effects

The most commonly reported grade 3 or 4 adverse events were chest pain (3%) and anemia (2%) in the MesoPher/best supportive-care group, and shortness of breath, chest pain, nausea, decreased appetite and pneumonia (2% each) in the best supportive-care-only group. Treatment-related infusion reactions occurred in 74% and injection-site reactions in 84% of patients receiving MesoPher/best supportive care; all were grade 1 or 2. Serious adverse events occurred in 8% versus 9% of patients. No patient discontinued treatment because of adverse events. No treatment-related deaths were reported.

Conclusion

MesoPher, a dendritic cell vaccine, did not improve overall survival in pleural mesothelioma. Immune checkpoint therapy is currently standard treatment for this disease. Further randomized trials are needed to determine whether combining MesoPher with immune checkpoint therapy can improve effectiveness without adding major toxicities.