Rationally combining immunotherapies to improve efficacy of immune checkpoint blockade in solid tumors

Cytokine Growth Factor Rev. 2017 Aug;36:5-15. doi: 10.1016/j.cytogfr.2017.06.011. Epub 2017 Jun 28.


With the widespread application of immune checkpoint blocking antibodies (ICBs) for the treatment of advanced cancer, immunotherapy has proven to be capable of yielding unparalleled clinical results. However, despite the initial success of ICB-treatment, still a minority of patients experience durable responses to ICB therapy. A plethora of mechanisms underlie ICB resistance ranging from low immunogenicity, inadequate generation or recruitment of tumor-specific T cells or local suppression by stromal cells to acquired genetic alterations leading to immune escape. Increasing the response rates to ICBs requires insight into the mechanisms underlying resistance and the subsequent design of rational therapeutic combinations on a per patient basis. In this review, we aim to establish order into the mechanisms governing primary and secondary ICB resistance, offer therapeutic options to circumvent different modes of resistance and plea for a personalized medicine approach to maximize immunotherapeutic benefit for all cancer patients.

Keywords: Immune-checkpoint blockade; Immunotherapy; Personalized medicine; Tumor immunology; Tumor microenvironment.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism
  • Humans
  • Immunotherapy / methods*
  • Immunotherapy / trends
  • Mice
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Precision Medicine
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment


  • Antibodies, Monoclonal
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor