Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI. METHODS: Biopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm2. Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria. RESULTS: Thirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies. CONCLUSION: Biopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM.

Nose in malignant mesothelioma-Prediction of response to immune checkpoint inhibitor treatment.

INTRODUCTION: Recent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However, there are no accurate biomarkers to predict who will respond. The aim of this study was to assess the accuracy of exhaled breath analysis using electronic technology (eNose) for discriminating between responders to ICI and non-responders. METHODS: This proof-of-concept prospective observational study was part of an intervention study (INITIATE) in patients with recurrent MPM who were treated with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4). At baseline and after six weeks of treatment, breath profiles were collected by an eNose. Modified Response Evaluation Criteria in Solid Tumors were used to assess efficacy at 6-month follow-up. For data processing and statistics, we used independent t-test analyses followed by linear discriminant and receiver-operating characteristic (ROC) analysis. RESULTS: Exhaled breath data of 31 MPM patients who received nivolumab plus ipilimumab were available at baseline. There were 16 with and 15 without a response after 6 months of treatment. At baseline, breath profiles significantly differed between responders and non-responders, with a cross validation value of 71%. The ROC-AUC after internal cross-validation was 0.90 (confidence interval: 0.80-1.00). CONCLUSION: An eNose is able to discriminate at baseline between responders and non-responders to nivolumab plus ipilimumab in MPM, thereby potentially identifying a subgroup of patients that will benefit from ICI treatment.

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.

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-γ producing TEMRAs 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.

Chemotherapy options versus "novel" therapies: how should we treat patients with malignant pleural mesothelioma.

Today there are several options for the treatment of patients with malignant pleural mesothelioma (MPM). The therapeutic arsenal has expanded from only chemotherapy with or without surgery in selected cases to a variety of new compounds that target the malignant cell or its micro-environment. Immunotherapy has been the latest achievement and now single arm and randomized studies are being presented. A renewed interest has occurred in the combination of surgery, chemotherapy and radiation therapy. In this review we present the available data on previous and running studies and try to give a recommendation how to select the best patient for the most optimal therapy.

Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial.

BACKGROUND: Single-drug checkpoint inhibition has shown efficacy in patients with recurrent malignant pleural mesothelioma. Here, we assessed the safety and efficacy of the combination of nivolumab, an anti-programmed cell death 1 antibody, plus ipilimumab, an anti-cytotoxic T-lymphocyte protein 4 antibody, in patients with previously treated and relapsed malignant pleural mesothelioma. METHODS: INITIATE was a prospective single-centre, single arm, phase 2 trial. Patients with malignant pleural mesothelioma who progressed after at least one line of platinum-containing chemotherapy were enrolled. Key eligibility criteria were measurable disease according to the modified Response Evaluation Criteria in Solid Tumours for mesotheliomas, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received intravenous nivolumab (240 mg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks up to four times). Treatment was continued for up to 2 years or until confirmed progression or unacceptable toxicity. The primary endpoint was disease control at 12 weeks. All patients who received at least one dose of therapy were included in safety analysis and all patients who received one dose of therapy and at least one radiological assessment were included in the primary analysis. This trial is registered at ClinicalTrials.gov, number NCT03048474. FINDINGS: Between Oct 5, 2016, and Aug 3, 2017, 38 patients were enrolled in the study, of which two patients were excluded because they were not eligible for a biopsy. Of 36 eligible patients, one deteriorated before the start of the study so was not included in any analyses and one withdrew consent after one treatment cycle before radiological assessment so was included in the safety population only. 34 patients were evaluable for response assessment at 12 weeks. Of these, ten (29%) patients had a partial response and 13 (38%) patients had stable disease; thus, disease control was achieved by 23 (68%, 95% CI 50-83) of 34 patients. Treatment-related adverse events were reported in 33 (94%) patients. The most common adverse events were infusion-related reactions, skin disorders, and fatigue. Grade 3 treatment-related adverse events were reported in 12 (34%) of 35 patients. INTERPRETATION: In this single-centre phase 2 trial, the combination of nivolumab plus ipilimumab showed marked efficacy in patients with recurrent malignant pleural mesothelioma. The safety profile was consistent with known data on the combination regimen. Our results warrant further investigation of this combination in a phase 3 trial. FUNDING: Bristol-Myers Squibb.