Immune Checkpoint inhibitors: An introduction to the next‐generation cancer immunotherapy

Abstract

Activating the immune system to eliminate cancer cells and produce clinically relevant responses has been a long-standing goal of cancer research. Most promising therapeutic approaches to activating antitumor immunity include immune checkpoint inhibitors. Immune checkpoints are numerous inhibitory pathways hardwired in the immune system. They are critical for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage. Tumors regulate certain immune checkpoint pathways as a major mechanism of immune resistance. Because immune checkpoints are initiated by ligand-receptor interactions, blockade by antibodies provides a rational therapeutic approach. Although targeted therapies are clinically successful, they are often short-lived due to rapid development of resistance. Immunotherapies offer one notable advantage. Enhancing the cell-mediated immune response against tumor cells leads to generation of a long-term memory lymphocyte population patrolling the body to attack growth of any new tumor cells, thereby sustaining the therapeutic effects. Furthermore, early clinical results suggest that combination immunotherapies offer even more potent antitumor activity. This review is intended to provide an introduction to immune checkpoint inhibitors and discusses the scientific overview of cancer immunotherapy, mechanisms of the inhibitors, clinical pharmacology considerations, advances in combination therapies, and challenges in drug development.

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

“…J Clin Pharmacol. 2015:56 20 ; permission conveyed through Copyright Clearance Center, Inc. melanoma. 10,22,25 Nivolumab was first approved by the Japan Pharmaceuticals and Medical Devices Agency in July 2014 and by the FDA in December 2014 for the treatment of patients with unresectable or metastatic melanoma, initially for second-line treatment after failure of ipilimumab (and also after a BRAF inhibitor in patients positive for BRAF V600 mutation).…”

“…18 CTLA-4 and PD-1/PD-L1 have complementary and synergistic roles in regulating T-cell activation ( Figure 2). 19,20 CTLA-4 acts as a coinhibitory receptor of the CD28-B7 axis, which has a critical role in T-cell response and in cancer escape of tumor surveillance; blocking this pathway prevents induction of tolerance and increases activated T-cell number and repertoire. 18,19,21 Anti-CTLA-4 ipilimumab was the first immuno-oncology therapy to show overall survival (OS) benefit in metastatic melanoma compared with the standard of care, 10,22 and in 2011 ipilimumab initiated the rise of checkpoint inhibitors as cancer therapy ( Figure 1).…”

Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab

“…1 Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), specifically ipilimumab, and programmed cell death protein 1 (PD-1), nivolumab and pembrolizumab, and the combination of ipilimumab with nivolumab have been Food and Drug Administration (FDA)-approved for the treatment of metastatic melanoma. [2][3][4] In the European Union, ipilimumab was approved for metastatic melanoma in 2013, 5 with pembrolizumab and nivolumab approved within the past year.…”

Receptor occupancy by flow cytometry

“…This novel class of compounds includes small molecules and biologics whose mechanism of action can include harnessing the power of the immune system or depleting target cells associated with disease pathology. Immunotherapy is thought to represent a turning point in cancer treatment, and promises to be of considerable benefit to patients with inflammatory and immunologically based diseases as well (1)(2)(3).…”