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

Abstract

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-III 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 CD8 T cells and high frequencies of effector memory CD8 T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-g 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. Funding: Bristol-Myers Squibb sponsored NivoMes and INITIATE clinical trials and provided study drugs. No external funding was applicable for the flow cytometric analyses of peripheral blood samples described in this manuscript.

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

“…The INITIATE trial (Table 4 ) which had an estimated OS of approximately 12.7 months (Table 4 ) [ 72 – 74 ] along with the NivoMes trial (Table 3 ) were recently re-examined to complete a comprehensive immune cell profiling of samples [ 74 ], and the results demonstrated that the combination therapy induced a profound increase in the proliferation and activation of effector memory T cells which was not observed in the monotherapy, suggesting a clear benefit for the combination therapy, and therefore this observation warrants a larger Phase III trials of this combination therapy in the salvage setting.…”

Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics

“…Nivolumab, an IgG4 mAb against PD-1, was approved following the pivotal trial CheckMate-037, on December 22, 2014, for the treatment of patients with unresectable of metastatic melanoma who have experienced disease progression following ipilimumab and, if BRAF V600 mutation-positive, a BRAF inhibitor. Between 2015 and 2020, new indications were approved for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy ( 49 , 50 ), for treatment in combination with ipilimumab or as a single agent for unresectable or metastatic melanoma patients ( 51 ), for the treatment of patients with advanced renal cell carcinoma ( 52 ), classical Hodgkin’s lymphoma ( 53 ), recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) ( 54 ), locally advanced or metastatic urothelial carcinoma, hepatocellular carcinoma ( 55 ), metastatic SCLC ( 56 ), metastatic or recurrent NSCLC ( 57 ), esophageal squamous cell carcinoma (ESCC) ( 58 ), and for patients with unresectable malignant pleural mesothelioma ( 59 , 60 ).…”

Malignant Pleural Effusions—A Window Into Local Anti-Tumor T Cell Immunity?

“…The ability of T cells to produce effector molecules ex vivo is a measure of T cell effector function. Understanding the effector status of T cells is important as ICB induces activation and proliferation of circulating and intratumoral T cells which correlates with response ( 78 , 79 ). While MPE CD8 + T cells can produce IFN γ , granzyme B and perforin ex vivo , the frequency of MPE T cells that secrete these molecules is reduced compared to T cells from matched peripheral blood samples ( 67 , 70 ).…”