Tocilizumab and immune signatures for targeted management of cytokine release syndrome in immune checkpoint therapy

Ann Oncol. 2025 Apr;36(4):444-459. doi: 10.1016/j.annonc.2024.12.004. Epub 2024 Dec 17.

Abstract

Background: This study aimed to identify specific biomarkers in oncology patients experiencing immune-related cytokine release syndrome (irCRS)-like symptoms during immune checkpoint inhibitor (ICI) therapy, including severe cases like hemophagocytic lymphohistiocytosis (irHLH), and to distinguish these from sepsis. A secondary objective was to retrospectively analyze the efficacy of tocilizumab (TCZ) in treating corticosteroid (CS)-refractory high-grade irCRS.

Patients and methods: A cohort of 35 patients presenting with irCRS-like symptoms was studied, including 9 with irHLH-like manifestations and 8 with sepsis. Immune profiling was carried out using 48 mass cytometry markers, along with an analysis of 45 serum biomarkers, including 27 cytokines and 18 additional markers from the HScore. Twelve patients with high-grade irCRS refractory to CS were treated with TCZ.

Results: Twenty-four biomarkers significantly distinguished between irHLH and grade 3 irCRS (P = 0.0027-0.0455). Hepatocyte growth factor (HGF) and ferritin had superior predictive values compared with the traditional HScore, both with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. CXCL9 differentiated irHLH from grade 3 irCRS and predicted the need for TCZ treatment intensification (PPV = 90%, NPV = 100%). Additional biomarkers, including leukocyte count, neutrophils, ferritin, interleukin (IL)-6, IL-7, epidermal growth factor, fibrinogen, and granulocyte-macrophage colony-stimulating factor (GM-CSF), discriminated sepsis from high-grade irCRS (PPV = 75%-80%, NPV = 100%). Elevated frequencies of CXCR5+ or CCR4+ CD8 memory cells, CD38+ intermediate monocytes, and CD62L+ neutrophils were observed in high-grade irCRS compared with sepsis. All 12 patients with high-grade irCRS refractory to CS treated with TCZ experienced complete resolution.

Conclusions: This study highlights the importance of specific immunologic biomarkers in determining irCRS severity, predicting outcomes, and distinguishing between irHLH, irCRS, and sepsis. It also demonstrates the efficacy of TCZ in managing high-grade irCRS, underscoring the need for personalized therapeutic strategies based on these biomarkers.

Keywords: biomarkers; cytokine release syndrome; hemophagocytic lymphohistiocytosis; immune checkpoint inhibitors; immune profiling; sepsis.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Biomarkers / blood
  • Cytokine Release Syndrome* / blood
  • Cytokine Release Syndrome* / chemically induced
  • Cytokine Release Syndrome* / diagnosis
  • Cytokine Release Syndrome* / drug therapy
  • Cytokine Release Syndrome* / immunology
  • Cytokines / blood
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / adverse effects
  • Lymphohistiocytosis, Hemophagocytic* / blood
  • Lymphohistiocytosis, Hemophagocytic* / chemically induced
  • Lymphohistiocytosis, Hemophagocytic* / diagnosis
  • Lymphohistiocytosis, Hemophagocytic* / drug therapy
  • Lymphohistiocytosis, Hemophagocytic* / immunology
  • Male
  • Middle Aged
  • Neoplasms* / drug therapy
  • Neoplasms* / immunology
  • Retrospective Studies
  • Sepsis / blood
  • Sepsis / diagnosis
  • Sepsis / drug therapy
  • Sepsis / immunology

Substances

  • tocilizumab
  • Antibodies, Monoclonal, Humanized
  • Immune Checkpoint Inhibitors
  • Biomarkers
  • Cytokines