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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Immunol. Mar 27, 2015; 5(1): 1-15
Published online Mar 27, 2015. doi: 10.5411/wji.v5.i1.1
Present and future of immune checkpoint blockade: Monotherapy to adjuvant approaches
Mira A Patel, Jennifer E Kim, Jacob Ruzevick, Michael Lim
Mira A Patel, Jennifer E Kim, Jacob Ruzevick, Michael Lim, Department of Neurosurgery, the Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
Michael Lim, Department of Oncology, the Johns Hopkins University School of Medicine Baltimore, MD 21287, United States
Author contributions: Patel MA and Kim JE contributed equally to this work; Ruzevick J and Lim M reviewed this work.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Michael Lim, MD, Associate Professor of Neurosurgery and Oncology, Department of Neurosurgery, the Johns Hopkins University School of Medicine, 600 N. Wolfe St., Phipps Building Rm 123, Baltimore, MD 21287, United States. mlim3@jhmi.edu
Telephone: +1-410-614627 Fax: +1-410-5024954
Received: June 30, 2014
Peer-review started: July 1, 2014
First decision: September 28, 2014
Revised: October 23, 2014
Accepted: November 17, 2014
Article in press: November 19, 2014
Published online: March 27, 2015
Processing time: 273 Days and 12.6 Hours
Abstract

Immune regulation of aggressive tumor growth is often outpaced by tumor up-regulation of ligands that inhibit effector immune responses through the activation of immune checkpoints. A few of such checkpoints include programmed death-1 (PD-1), cytotoxic T lymphocyte associated antigen-4 (CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin and mucin protein-3, Glucocorticoid-induced TNFR family-related receptor (GITR), and killer cell immunoglobulin like receptor. With the exception of GITR, after binding to their respective ligands these checkpoints induce down-modulation of immune responses to prevent autoimmunity. However, such immune mechanisms are co-opted by tumors to allow rapid tumor cell proliferation. Pre-clinical studies in antibody blockade of PD-1 and CTLA-4 have led to promising augmentation of effector immune responses in murine tumor models, and human antibodies against PD-1 and CTLA-4 alone or in combination have demonstrated tumor regression in clinical trials. The development of immune checkpoint blockade as a potential future immunotherapy has led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemotherapy and radiation therapy has shown synergistic effects in pre-clinical and clinical studies, and combination checkpoint blockade with bacterial vaccine vectors have produced increased effector immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.

Keywords: Programmed death-1; Cytotoxic T lymphocyte associated antigen-4; Ipilimumab; Nivolumab; Immune checkpoint

Core tip: Aggressive cancer growth is often characterized by tumor expression of molecules that co-opt effective immune responses through immune checkpoints. Clinical blockade of checkpoints programmed death-1 and cytotoxic T lymphocyte associated antigen-4 and has spurred the discovery of a number of immune checkpoints that may be inhibited in anticancer therapy. The clinical successes of checkpoint blockade have led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemoradiation has shown synergistic effects, and checkpoint blockade with bacterial vaccine vectors have produced increased immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.