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
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.
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.