Immunotherapy for Pleural Mesothelioma: Does it Work?

Immunotherapy is an important emerging therapeutic strategy for several types of cancer, but the jury is still out on whether it will eventually be a viable approach for malignant pleural mesothelioma.

In a newly-published special report on the immune checkpoint inhibitor tremelimumab, researchers at the University of Salford in the UK call the use of such drugs “largely questionable” for pleural mesothelioma treatment.

Their concerns, they say, not only have to do with clinical efficacy, but also extend to the safety and tolerability of immunotherapy drugs like tremelimumab in mesothelioma patients.

Immune Checkpoint Inhibitors in Mesothelioma Treatment

Tremelimumab is an immune checkpoint inhibitor designed to interrupt a mechanism that helps mesothelioma cells “hide” from attack by the immune system.

By binding to a protein called CTLA-4, which is expressed on the surface of T lymphocytes, tremelimumab allows these immune system cells to recognize and kill mesothelioma cells. Other types of immune checkpoint inhibitors may block other cell surface proteins such as PD-1.

The problem is that, in malignant mesothelioma, this blocking mechanism is only moderately effective. While early studies of tremelimumab in mesothelioma therapy produced some encouraging results, later studies have been mixed.

A 2015 meta-analysis of studies of tremelimumab and another CTLA-4 blocker concluded that these drugs tended to trigger immune related adverse events in mesothelioma patients.

Immunotherapy Drugs Cannot Go it Alone

In an earlier study in 2015, the Salford team expressed uncertainty about what they called the “cost/benefit ratio” of tremelimumab for mesothelioma. In their newest analysis of anti-CTLA-4 therapy for malignant mesothelioma, the team observes that, at the very least, tremelimumab cannot fight the asbestos cancer by itself.

“Biological and clinical considerations rule out the use of tremelimumab as single agent for malignant mesothelioma,” writes lead researcher Alice Guazzelli. “More generally, the use of immune checkpoint inhibitors for malignant mesothelioma is still largely questionable and not supported by evidences.”

An Australian study published in the fall of 2016 called the recent studies on checkpoint inhibitors for mesothelioma “disappointing” and said these drugs “will need to be used in combination approaches with other immunotherapies, vaccines, or chemotherapy.”

Mesothelioma News is Better for PD-1 Inhibitors

But the news has been somewhat more promising for immune checkpoint inhibitors that block the cell surface protein PD-1. Pembrolizumab (Keytruda), avelumab, and nivolumab are three PD-1/PD-L1 inhibitors that made headlines in the treatment of mesothelioma in 2016.

The KEYNOTE trial of pembrolizumab, which included 25 malignant pleural mesothelioma patients, found a 20 percent overall response rate and a median response duration of a year.

Avelumab produced a mesothelioma control rate of 56.6% and previously-treated Dutch mesothelioma patients given nivolumab had a median survival of more than a year. Studies are ongoing on these and a number of other immunotherapy drugs.

Malignant pleural mesothelioma is a rare and highly invasive cancer that is closely related to asbestos exposure. The current median survival time with standard cancer treatments is less than 12 months.

Sources:

Guazzelli, A, et al, “Anti-CTLA-4 therapy for malignant mesothelioma”, March 2017, Immunotherapy, pp. 273-280

Thapa, B, et al, “Immunotherapy for malignant mesothelioma: reality check”, October 2016, Expert Review of Anticancer Therapy, Epub ahead of print

“Nivolumab Shows Promise in Treating Malignant Pleural Mesothelioma”, International Association for the Study of Lung Cancer, News Release, December 7, 2016