The evolution of checkpoint blockade as a cancer therapy: what's here, what's next?

Curr Opin Immunol. 2015 Apr;33:23-35. doi: 10.1016/j.coi.2015.01.006. Epub 2015 Jan 23.

Abstract

Unleashing the immune system to fight cancer has become one of the main treatment modalities since the anti-CTLA-4 antibody, ipilimumab was approved for patients with advanced melanoma in 2011. Pembrolizumab and nivolumab, two anti-PD-1 antibodies recently approved for the treatment of patients with metastatic melanoma, are being actively investigated for the treatment of multiple caners including lung, breast, bladder and renal cancers along with other anti-PD-1/L1 antibodies. Early results of combining of anti-CTLA-4 antibody and anti-PD-1 antibody treatment for advanced melanoma patients are showing impressive response rates with manageable toxicity profiles. There are several other checkpoint molecules that are likely potential inhibitory targets. The outcome of blocking some of these negative immune regulators, such as LAG-3 or TIM-3, is being pursued in the clinic or about to enter clinical development. Blockade of these molecules is demonstrating promising preclinical activity alone or when combined with anti-PD-1/L1. Future studies will define bio-markers of these therapies and how to target them alone or in combination with other immunotherapies, chemotherapy, radiotherapy and small molecule inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • Clinical Trials as Topic
  • Costimulatory and Inhibitory T-Cell Receptors / antagonists & inhibitors
  • Drug Evaluation, Preclinical
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antineoplastic Agents
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Costimulatory and Inhibitory T-Cell Receptors
  • Programmed Cell Death 1 Receptor