Clinical drug screening reveals clofazimine potentiates the efficacy while reducing the toxicity of anti-PD-1 and CTLA-4 immunotherapy

Gang Xue, Xin Li, Muhammad Kalim, Jing Fang, Zhiwu Jiang, Ningbo Zheng, Ziyu Wang, Xiaoyin Li, Maen Abdelrahim, Zhiheng He, Mikhail Nikiforov, Guangxu Jin, Yong Lu

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Emerging as the most potent and durable combinational immunotherapy, dual anti-PD-1 and CTLA-4 immune checkpoint blockade (ICB) therapy notoriously increases grade 3–5 immune-related adverse events (irAEs) in patients. Accordingly, attempts to improve the antitumor potency of anti-PD-1+CTLA-4 ICB by including additional therapeutics have been largely discouraged due to concerns of further increasing fatal toxicity. Here, we screened ∼3,000 Food and Drug Administration (FDA)-approved drugs and identified clofazimine as a potential third agent to optimize anti-PD-1+CTLA-4 ICB. Remarkably, clofazimine outperforms ICB dose reduction or steroid treatment in reversing lethality of irAEs, but unlike the detrimental effect of steroids on antitumor efficacy, clofazimine potentiates curative responses in anti-PD-1+CTLA-4 ICB. Mechanistically, clofazimine promotes E2F1 activation in CD8+ T cells to overcome resistance and counteracts pathogenic Th17 cells to abolish irAEs. Collectively, clofazimine potentiates the antitumor efficacy of anti-PD-1+CTLA-4 ICB, curbs intractable irAEs, and may fill a desperate clinical need to improve patient survival.

Original languageEnglish (US)
Pages (from-to)780-796.e6
JournalCancer Cell
Volume42
Issue number5
Early online dateMar 19 2024
DOIs
StatePublished - May 13 2024

Keywords

  • Animals
  • CD8-Positive T-Lymphocytes/drug effects
  • CTLA-4 Antigen/antagonists & inhibitors
  • Cell Line, Tumor
  • Clofazimine/pharmacology
  • Humans
  • Immune Checkpoint Inhibitors/adverse effects
  • Immunotherapy/methods
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor/antagonists & inhibitors
  • Th17 Cells/drug effects

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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