Next generation of immune checkpoint therapy in cancer: New developments and challenges

Julian A. Marin-Acevedo, Bhagirathbhai Dholaria, Aixa E. Soyano, Keith L. Knutson, Saranya Chumsri, Yanyan Lou

Research output: Contribution to journalReview article

154 Scopus citations

Abstract

Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

Original languageEnglish (US)
Article number39
JournalJournal of Hematology and Oncology
Volume11
Issue number1
DOIs
StatePublished - Mar 15 2018

Keywords

  • Cancer
  • Co-stimulatory pathways
  • Cytotoxic T lymphocytes
  • Immune checkpoint therapy
  • Immune evasion
  • Immunotherapy
  • Immunotherapy
  • Inhibitory pathways
  • Tumor microenvironment
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

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