Abstract
Recent progress in cancer immunotherapy has been remarkable. Most striking are the clinical development and approval of immunomodulators, also known as immune checkpoint inhibitors. These monoclonal antibodies (mAb) are directed to immune checkpoint molecules, which are expressed on immune cells and mediate signals to attenuate excessive immune reactions. Although mAbs targeting tumor associated antigens, such as anti-CD20 mAb and anti-Her2 mAb, directly recognize tumor cells and induce cell death, immune checkpoint inhibitors restore and augment the antitumor immune activities of cytotoxic T cells by blocking immune checkpoint molecules on T cells or their ligands on antigen presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of immune checkpoint inhibitors in a variety of cancers. The first in class approved immune checkpoint inhibitor is ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) mAb. Two pivotal phase III randomized controlled trials demonstrated a survival benefit in patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved ipilimumab for metastatic melanoma. Several clinical trials have since investigated new agents, alone and in combination, for various cancers. In this review, we discuss the current development status of and future challenges in utilizing immune checkpoint inhibitors.
Highlights
In this decade, remarkable progress has been made in the clinical application of cancer immunotherapies
We focus on the current development status of and future challenges in utilizing immune checkpoint inhibitors, especially cytotoxic T lymphocyte antigen-4 (CTLA-4), PD-1, and PD-L1
Immune checkpoint inhibitors have opened a new era of cancer immunotherapy
Summary
Remarkable progress has been made in the clinical application of cancer immunotherapies. Costimulatory/inhibitory molecules mediate positive/negative signals that modify MHC-TCR (major histocompatibility complex-T-cell receptor) signaling pathways. These signals each regulate T-cell survival, proliferation, differentiation, or responsiveness to cognate antigens. Coinhibitory molecules induce T-cell dysfunction (so called “T-cell exhaustion”) or apoptosis Employing this inhibitory pathway, the immune system can attenuate excessive immune reactions and ensure self-tolerance, which is important for maintaining immune homeostasis. The immune system can attenuate excessive immune reactions and ensure self-tolerance, which is important for maintaining immune homeostasis These functions involve programmed cell death protein-1 (PD-1), programmed cell death-1 ligand-1/2 (PD-L1/2), cytotoxic T lymphocyte antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin mucin-3 (TIM-3), and B and T lymphocyte attenuator (BTLA). We focus on the current development status of and future challenges in utilizing immune checkpoint inhibitors, especially CTLA-4, PD-1, and PD-L1
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