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

D Daoudlarian; A Segot; S Latifyan; R Bartolini; V Joo; N Mederos; H Bouchaab; R Demicheli; K Abdelhamid; N Ferahta; J Doms; G Stalder; A Noto; L Mencarelli; V Mosimann; D Berthold; A Stravodimou; C Sartori; K Shabafrouz; J A Thompson; Y Wang; S Peters; G Pantaleo; M Obeid

doi:10.1016/j.annonc.2024.12.004

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

Ann Oncol. 2024 Dec 17:S0923-7534(24)04979-2. doi: 10.1016/j.annonc.2024.12.004. Online ahead of print.

Authors

D Daoudlarian¹, A Segot², S Latifyan³, R Bartolini¹, V Joo¹, N Mederos³, H Bouchaab³, R Demicheli³, K Abdelhamid³, N Ferahta³, J Doms¹, G Stalder⁴, A Noto¹, L Mencarelli¹, V Mosimann³, D Berthold³, A Stravodimou³, C Sartori⁵, K Shabafrouz³, J A Thompson⁶, Y Wang⁷, S Peters³, G Pantaleo¹, M Obeid⁸

Affiliations

¹ Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Service, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
² Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Oncology, Service and Central Laboratory of Hematology, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
³ Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Oncology, Medical Oncology Service, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
⁴ Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Oncology, Service and Central Laboratory of Hematology, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland; Service of Hematology, Institut Central des Hôpitaux, Hôpital du Valais, Av. du Grand-Champsec 86, CH-1951 Sion, Switzerland.
⁵ Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of medicine, internal medicine service, Rue du Bugnon 17, CH-1011 Lausanne, Switzerland.
⁶ Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
⁷ Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Department of Medicine, Immunology and Allergy Service, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland. Electronic address: michel.obeid@chuv.ch.

PMID: 39701282
DOI: 10.1016/j.annonc.2024.12.004

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 performed 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: 24 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 to 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, IL-6, IL-7, EGF, fibrinogen, and 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 to 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: Immune profiling; biomarkers; cytokine release syndrome; decision tree; hemophagocytic lymphohistiocytosis; immune checkpoint inhibitors; sepsis.