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T. Seiwert
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.12 - Multiplex Immunofluorescence Identifies Differences in Immune Microenvironment & Prognostic Biomarkers between Mesothelioma Subtypes (ID 3217)
18:30 - 20:00 | Author(s): T. Seiwert
- Abstract
- Presentation
Background:
Malignant mesothelioma (MM) is a universally lethal disease, which develops in the pleura, peritoneum, pericardium, and tunica vaginalis. MM is commonly associated with a prominent inflammatory reaction, including extensive macrophage infiltration. Early reports indicate presence of tumor infiltrating lymphocytes (TILs), PD-L1 expression (Kindler et al ASCO 2014), and activity of anti-PD-1 therapy (Alley et al AACR 2015). However, quantitative evaluation of multiple immune markers in a large mesothelioma cohort and evaluation of prognostic and biologic implications has not been reported.
Methods:
We performed multiplex immunofluorescence (IF) staining and automated, quantitative density assessments in a clinically annotated cohort of 109 malignant mesotheliomas (58 epithelioid, 43 biphasic, 8 sarcomatoid). Staining for PD-1, PD-L1 (immune checkpoint), FOXP3 (T-regulatory cells), and CD8 (TILs) was performed using a quantitative, multiplex IF system (TissueFax), and a multi-tumor-validated, quantitative StrataQuest analysis algorithm in order to identify specific immune cells and respective densities. Gene expression data (TCGA) was analyzed to confirm individual correlations. Staining for CD206 (macrophages) is ongoing.
Results:
PD-L1 density correlated with more aggressive histology, and was highest in sarcomatoid (median density score of 3016), and biphasic (2720) tumors compared with epithelioid tumors (1740). Using a cutoff of 5% PD-L1 density by area 19% of epithelioid, 38% of sarcomatoid, and 44% of biphasic tumors were deemed PD-L1 positive. PD-L1 expression exhibited a bimodal distribution (peaks at both high and low PD-L1 densities). Also with the biphasic tumor cohort expression of PD-L1 correlated with worse outcome (P=0.02), while PD-1 and CD8 did not have prognostic implications (and could not distinguish histologic subtypes). By contrast in epithelioid MM CD8 infiltration density showed a trend towards improved prognosis (P=0.06) (and correlated with PD-1 expression), while PD-L1 expression was not prognostic. Interestingly, PD-1/CD8 and PD-L1 expression did not correlate regardless of histology (R=0.02-0.08), suggesting macrophage-driven PD-L1 expression. Gene expression data supported this hypothesis and staining for M2-related macrophage markers is ongoing. In epithelioid tumors FOXP3 T-regulatory cell density showed a trend towards worse prognosis (P=0.07). In biphasic and sarcomatoid tumors prognosis was poor regardless of FOXP3 expression. Data on stromal versus tumor expression patterns is being processed.
Conclusion:
In mesothelioma CD8, PD-1, PD-L1 and FOXP3 are widely expressed, with 19% of epithelioid, and 38-44% of sarcomatoid and biphasic tumors showing elevated PD-L1 density. PD-L1 expression correlates with a worse prognosis by subtype and in the biphasic tumor population. In epithelioid tumors PD-1 may indicate better outcome. PD-1 and PD-L1 expression do not correlate with each other in malignant mesothelioma, which relates to pro-tumorigenic macrophages leading to potentially interferon gamma independent PD-L1 expression.
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P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.08-010 - Phase II Study of the Anti-PD-1 Antibody Pembrolizumab in Patients with Malignant Mesothelioma (ID 3020)
09:30 - 17:00 | Author(s): T. Seiwert
- Abstract
Background:
Mesothelioma is a frequently "inflamed" tumor. We previously identified PD-L1 expression, a CD8 infiltrative pattern, and the presence of PD-1/PD-L1 immune checkpoints in about 1/3 of mesothelioma tumors, similar to the phenotype found in malignancies such as melanoma that benefit from immune checkpoint blockade (Kindler and Seiwert, ASCO 2014). Based on these data, we have initiated a single-center phase II trial (NCT02399371) of the anti-PD-1 antibody pembrolizumab in previously-treated mesothelioma patients. The rationale for this study is further supported by recent data from a phase IB multi-cohort study of pembrolizumab in PD-L1 positive solid tumors, in which an objective response rate of 28% and a disease control rate of 76% was observed in 25 pleural mesothelioma patients, who received 10 mg/kg pembrolizumab every 2 weeks (Alley, AACR 2015).
Methods:
Eligible patients have histologically-confirmed pleural or peritoneal mesothelioma, measurable disease, PS 0-1, disease progression on or after treatment with pemetrexed plus cis- or carboplatin, no more than 2 prior lines of cytotoxic therapy, normal organ function, and tissue available for correlative studies. Patients receive a flat dose of 200 mg pembrolizumab intravenously every 3 weeks. CT scans are obtained every 9 weeks. The primary objectives are: 1) to determine the objective response rate in A] an unselected population and in B] a PD-L1 positive population, and 2) to determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay. Secondary objectives include progression-free and overall survival, disease control rate, and toxicity. Correlative studies are intended to characterize the T-cell inflamed phenotype in mesothelioma via CD8, CD4, and PD-L1 staining, immune related gene expression signatures (Nanostring), and determination of other immune escape mechanisms including T-regulatory cells (FOXP3 expression), IDO expression, MDSCs, and other checkpoints/co-stimulatory signals by immunohistochemistry and/or flow cytometry. A single-stage binomial design will be used. Part A requires ≥ 3 responses in 35 patients. Part B, which uses PD-L1 pre-selection (optimal expression pattern and threshold determined in cohort A), requires ≥ 6 responses in 30 patients. Funded in part by a grant from the Mesothelioma Applied Research Foundation.
Results:
Not applicable.
Conclusion:
Not applicable.
