Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: translational evidence from two clinical trials

Mankor, J.M.; Disselhorst, M.J.; Poncin, M.; Baas, P.; Aerts, J.G.J.V.; Vroman, H. (2020)

Article / Letter to editor

Background: Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD-1 monotherapy failed to provide benefit in phase-Ill trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM.Methods: Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474).Findings: aPD-1 /aCTLA-4 combination treatment induced a profound increase in proliferation and activation of T cells, which was not observed upon aPD-1 monotherapy. Moreover, patients that responded to combination treatment had low frequencies of naive CDS T cells and high frequencies of effector memory CDS T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-y producing TEM-RAs was also higher in responding patients.Interpretation: High proportions of TEMRAs and cytokine production by TEMRAs before treatment, was associated with a better clinical outcome. TEMRAs, which likely comprise tumor-specific T cells, tend to require blockage of both aPD-1 and aCTLA-4 to be reactivated. In conclusion, peripheral blood TEMRAs can play a key role in explaining and predicting clinical benefit upon aPD-1/aCTLA-4 combination treatment. (C) 2020 Published by Elsevier B.V.

• Malignant pleural mesothelioma
• Immune checkpoint inhibitors
• Immunotherapy
• Immune monitoring
• Nivolumab
• Ipilimumab

• All authors: Mankor, J.M.; Disselhorst, M.J.; Poncin, M.; Baas, P.; Aerts, J.G.J.V.; Vroman, H.
• Date: 2020-12-01
• Journal: EBioMedicine
• Volume: 62
• DOI: doi:10.1016/j.ebiom.2020.103040
• Link: https://www.sciencedirect.com/science/article/pii/S2352396420304163?via%...