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 articlepeer-review

267 Scopus citations


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
Issue number1
StatePublished - Mar 15 2018


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

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research


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