Esophageal either or both PD-L1 and PD-L2.

Esophageal
cancer is a lethal disease with limited treatment options, particularly in the
metastatic setting. While the incidence of esophageal squamous cell carcinoma (ESCC)
has declined worldwide, it remains a major cause of morbidity and mortality in
Asia, Africa and South America (1). In contrast to esophageal adenocarcinoma, which develops
in the lower esophagus and is related to gastric reflux and Barrett’s
esophagus, ESCC occurs in the upper/mid esophagus and is associated with tobacco
and alcohol use (2). Despite their differences, a common feature of both ESCC and
adenocarcinoma is the presence of chronic inflammation and an abundance of
tumor-infiltrating lymphocytes and other immune cell populations. As shown in
other malignancies, infiltration of the tumor by CD8+ T cells was associated with
improved outcomes (3,4), while the presence of regulatory T cells and
myeloid-derived suppressor cells was correlated with worse overall survival (5,6). Furthermore, a small number of studies have evaluated the
role of immune inhibitory signals, specifically the programmed cell death-1
(PD-1) protein and its ligands PD-L1 and PD-L2, in ESCC. One such study used
gene expression to investigate the clinical significance of PD-L1 and PD-L2 in 41
cases of ESCC.  In this series, 43.9% of
patients had PD-L1 or PD-L2-positive tumors, determined by real-time
quantitative PCR.  PD-L1 and PD-L2
positivity was found to be a poor prognostic factor, in both univariate and
multivariate analysis (7). A more recent study confirmed these findings. Of 106
patients with ESCC who underwent surgery without prior chemotherapy or
radiation, 63 (59.4%) had tumors positive for either or both PD-L1 and PD-L2. PD-L1
and PD-L2 positivity predicted for worse overall survival (8). Furthermore, PD-L1 positivity has been associated with
advanced stage, nodal metastasis, poor response to neoadjuvant chemoradiotherapy
and locoregional recurrence (9).

 

Immune
checkpoint blockade has changed the treatment landscape for a variety of
cancers, most prominently melanoma, non-small cell lung cancer (NSCLC), renal
cell carcinoma and cancers. These marked successes have led to an increased
interest in evaluating these agents in several other malignancies. Given the high
unmet need for effective therapies in advanced or metastatic ESCC and its
prominent immunologic features, testing of immune checkpoint inhibitors in this
cancer was a reasonable step.

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Prior
to their evaluation in advanced ESCC, the anti-PD-1 antibodies nivolumab and
pembrolizumab demonstrated good efficacy in other squamous cancers and were FDA
approved for the treatment of metastatic squamous cell NSCLC and head and neck
squamous cell carcinoma (HNSCC). Specifically, nivolumab was compared with docetaxel
in a randomized phase III trial of patients with advanced squamous cell NSCLC
(CheckMate-017) (10). Nivolumab significantly improved the objective response
rate (ORR) (20% vs. 9%; P = 0.008) and prolonged the median OS (9.2 vs. 6.0
months; P