GYNECOLOGIC ONCOLOGY (A FADER, SECTION EDITOR)
Immune Checkpoint Inhibition in the Treatment of Gynecologic Cancer
Kristen Anderson, MD, PhD
Ramez N. Eskander, MD
Published online: 14 February 2018
Springer Science+Business Media, LLC, part of Springer Nature 2018
Purpose of Review The purpose of this review is to update readers on recent advancements in the use of immune checkpoint
inhibitors for the treatment of ovarian, uterine, and cervical cancers.
Recent Findings Immunotherapy has emerged as a novel therapeutic paradigm in the treatment of gynecologic malignancies.
Currently, immune checkpoint inhibitors are approved for use across five solid malignancies, with recent approval of
pembrolizumab in patients with MMR-deficient, recurrent, solid tumors in a disease site agnostic fashion. Phase 3 clinical trials
are being conducted in the gynecologic cancer arena to determine if checkpoint inhibition will improve oncologic outcomes.
Positive signals have been identified in ovarian cancer cohorts, both as single agents and in combination with other agents. It is
anticipated that immunotherapy will be effective in MMR-deficient endometrial cancers, and trials are in development to explore
these agents in the front line. Furthermore, the HPV-driven biology of cervical cancer suggests that immune checkpoint inhibition
may lead to clinical benefit.
Summary Immune checkpoint inhibitors represent a dynamic and exciting opportunity for patients with limited therapeutic
options. We eagerly await the results of ongoing phase 3 clinical trials that will inform practice patterns. In addition, emphasizing
translational end-points informing patient selection and response is critical.
Check point inhibition
On May 23, 2017, in a landmark decision, the U. S. Food and
Drug Administration (FDA) granted accelerated approval for
pembrolizumab use in microsatellite instability-high (MSI-
high) or mismatch repair (MMR)-deficient recurrent cancers.
This represented the first disease site agnostic drug approval
that was a biomarker dependent in solid tumors. It is antici-
pated that this paradigm shift in cancer treatment will continue
to catalyze the investigation of novel therapeutics across dis-
ease sites that are based on molecular markers.
Given the limited oncologic gains to date with traditional
cytotoxic chemotherapy, numerous clinical trials in the gyne-
cologic cancer arena are testing targeted biologic agents alone
and in combination with cytotoxic drugs. Blocking or
disrupting tumor angiogenesis, enhancing the anti-tumor im-
mune response, inhibiting proliferative pathways, and modu-
lating DNA repair activity to cause synthetic lethality repre-
sent a handful of the targets that are currently being explored.
Pembrolizumab, a humanized monoclonal antibody to the
PD-1 receptor, belongs to a class of relatively new cancer
therapies termed immune checkpoint inhibitors, which func-
tion by increasing the body’s immune response against cancer
cells. This is accomplished by “inhibiting the inhibitors” that
work to suppress the immune response to foreign cancer-
related neoantigens. Checkpoint inhibitors, as a class, exert
their immune-related effects through regulation of the T cell
response. Activated T cells express receptors that receive stim-
ulatory and inhibitory signals and respond to the sum of these
signals. PD-1 and CTLA-4 ligands favor T cell inactivation
when they bind to their respective receptors. Blockade of this
signaling pathway results in T cell stimulation, as demonstrat-
ed by anti-PD-1 blocking monoclonal antibodies.
Using in vitro model systems, robust T cell responses to
tumor antigens are easily elicited. However, in previous trials
examining traditional cytotoxic therapy across solid
This article is part of the Topical Collection on Gynecologic Oncology
* Ramez N. Eskander, MD
Division of Gynecologic Oncology, Department of Reproductive
Medicine, University of California San Diego Moores Cancer Center,
La Jolla, CA 92093, USA
Current Obstetrics and Gynecology Reports (2018) 7:6–19