The anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) monoclonal antibody, tremelimumab, showed encouraging clinical activity and acceptable tolerability in patients with chemotherapy-resistant malignant mesothelioma, according to study results published in The Lancet Oncology.
Results of the single-arm phase II study provide a solid foundation for the testing of tremelimumab, one of a new class of immunomodulatory monoclonal antibodies, in a large randomized phase II study.
Tremelimumab is a monoclonal antibody that targets the CTLA4, which is expressed on T cells after activation. Ligation of CTLA4 restricts ongoing T-cell costimulation and activation, thereby abrogating autoimmunity or antitumor immunity, and inducing tolerance, according to researchers. CTLA4 blockade with monoclonal antibody inhibitors reduces these negative regulatory signals and allows any endogenous antitumor response to proceed unopposed.
In the study, 29 patients with measurable, unresectable malignant mesothelioma and progressive disease after first-line platinum-based chemotherapy were intravenously administered 15 mg/kg of tremelimumab every 90 days. Patients received a median of two doses (range 1-9); There were no complete responses but two (7%) patients had a durable partial response.
The rate of disease control was 31%, median progression-free survival was 6.2 months, and median overall survival was 10.7 months, according to researchers. Analysis of blood samples showed that numbers of circulating CD4-positive inducible costimulatory (ICOS)-positive T cells increased following each dose of tremelimumab and peaked at around day 14 before declining to basal levels. Patients with above-median levels during the first cycle had significantly better survival than those with lower levels.
“Although preliminary, the clinical and immunological findings of this study warrant further investigation of tremelimumab in patients with malignant mesothelioma, a conclusion that is also supported by preclinical evidence suggesting a synergistic effect of CTLA4 blockade and chemotherapy in malignant mesothelioma,” the authors concluded.