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... Show moreBackground: 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. Show less
Malignant pleural mesothelioma (MPM) is a cancer of the pleura with few treatment options and an infaust prognosis. We developed a short-term primary tumor culture model from tumor cells derived... Show moreMalignant pleural mesothelioma (MPM) is a cancer of the pleura with few treatment options and an infaust prognosis. We developed a short-term primary tumor culture model from tumor cells derived from pleural fluid of MPM patients and performed drug screening on these cultures to guide treatment decisions of corresponding patients. We observed a high concordance between in vitro results and clinical outcomes and defined three subgroups responding differently to the anti-cancer drugs tested. Gene expression profiling yielded distinct signatures that segregated these subgroups and demonstrated that the fibroblast growth factor pathway was most prominently involved. Pharmacogenomic profiling revealed a subgroup of immortalized and primary MPM lines that appeared highly sensitive to FGFR inhibition. BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples. Furthermore, 34 patients were treated in a clinical trial with nivolumab which demonstrated meaningful clinical efficacy and a manageable safety profile in pretreated patients with mesothelioma. PD-L1 expression did not predict for response in this population. Show less
