Intensified Regimen of Tremelimumab Shows Efficacy, Safety in Clinical Trial

Early results from an ongoing clinical trial of advanced malignant mesothelioma treatment with a more intensive schedule of tremelimumab has shown clinical and immunological activity and a good safety profile, paving the way for further research into checkpoint inhibitor drugs.

“TheAnti-CTLA-4 Monoclonal Antibody Tremelimumab in Malignant Mesothelioma” is a clinical trial in Italy led by Luana Calabrò. Its purpose is to explore the efficacy of a more intensive schedule of treatment with tremelimumab in 29 malignant mesothelioma patients—28 with pleural mesothelioma and 1 with peritoneal mesothelioma.

A previous clinical study of melanoma patients treated with tremelimumab showed that, compared to standard of care chemotherapy, tremelimumab did not improve survival. It was theorized, however, that the negative findings were due to underexposure to the drug, which was given at 15 mg/kg every 90 days. Calabrò and colleagues therefore designed their study with an intensified regimen of tremelimumab 10 mg/kg once every 4 weeks for six doses.

Most patients maintained tremelimumab concentrations at or above the study target — a significantly better result than the predicate study. The more intensive tremelimumab regimen also produced more serious side effects in just two patients, indicating a very reasonable safety profile. The study met its primary endpoint by recording four patients achieving an immune-related response, indicating that the drug was active.

“Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile,” concluded the research team in an article published in The Lancet.

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According to the researchers, the same intensified schedule of tremelimumab is now being studied in mesothelioma patients in a more rigorous study.

About Tremelimumab and Monoclonal Antibodies

Tremelimumab, an immunotherapy drug that targets the T Cell receptor protein cytotoxic T-lymphocyte-associated protein 4 (CTLA4), belongs to a class of drugs that are known as “immune checkpoint inhibitors.”

T Cells are white blood cells that seek out and destroy faulty cells. CTLA4 is present on the surface of T Cells and helps to keep the immune system from becoming overactive and targeting healthy cells. Some cancer cells co-opt this inhibitory pathway as a means of immune resistance. In other words, the cancer cells take advantage of CTLA4 expression to tell the immune system to ignore them.

Anti-CTLA4 drugs such as tremelimumab block T Cells from being stopped by CTLA4. By blocking the immune checkpoint protein, T Cell anti-tumor response is enhanced.

To learn more about immune checkpoint inhibitors, check out this article in the journal Nature and this article from the MD Anderson Cancer Center.

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http://www.nature.com/nrc/journal/v12/n4/full/nrc3239.html