Deep mapping of the cytokine release syndrome inflammatory continuum: Comprehensive grade-specific profiling and differentiation from sepsis in patients receiving immune checkpoint therapy.
Authors: Obeid Michel , Daoudlarian Douglas , Segot Amandine , Latifyan Sofiya , Bouchaab Hasna , Mederos Nuria , Abdelhamid Karim , Ferahta Nabila , Stravodimou Athina , Shabafrouz Keyvan , Peters Solange , Pantaleo Giuseppe 
Published: July 2024

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Background: The delineation of cytokine release syndrome (irCRS) from sepsis and its transition to compensatory anti-inflammatory response syndrome (irCARS) is crucial during ICI therapy for personalized care. Methods: We conducted an extensive biological and immune profiling on PBMC and serum from 38 oncology patients with various irCRS grades, including immune-related hemophagocytic lymphohistiocytosis irHLH (n=9) and sepsis during ICI treatment (n=8). Results: Our results show a dominant Th1 response in irCRS. Early markers of irCRS increased progressively with clinical severity in different grades, especially CXCL9, CXCL10 and IFN-γ levels. Starting with low-grade (G) (G1 and 2), a concomitant irCARS response was detected, characterized by an initial increase in IL-1RA and a significant upregulation of IL-10 specifically in G4. 3 subclusters with different overall survival (OS) and cytokine profiles were identified using routine biomarkers. Cluster 1 (C1, n=7) and Cluster 2 (C2, n=17) showed a 2-year OS of 100% and 48.49%, respectively (HR=4.025 [95% CI = 1.052-15.39], p=0.0419) and differed with higher levels of CCL3/11, CXCL10 and Il-1RA. Cluster 3 (C3, n=3) had the lowest OS, 6-month OS of 0%, and a distinct biological profile with highest levels of CXCL8/12/13, IL1-RA, IL-6, IL-21, HGF, significantly different from C1 (HR=111.4 [95% CI=6.63-1871], p=0.0011) and C2 (HR=30.04 [95% CI=2.686-335.9], p=0.0256). In 12 patients with severe irCRS (G3 and 4) and refractory to steroids, treatment with tocilizumab (TCZ) resulted in 100% resolution. In irHLH patients (n=9), the clusters retained their prognostic impact. Similarly, in irHLH with poor prognosis (irHLH cluster 3, n=3), high levels of CXCL8/12/13, IL-6 and IL-21 were identified. 13 patients with sepsis-like symptoms (irHLH, n=8; or sepsis during ICI, n=5) showed distinct cytokine and immune cell profiles. irHLH showed elevated IL-1-RA, IL-10, IL-18, IFN-γ, CXCL9/10, CCL2/3/4 while sepsis was characterized by increased IL-7. In irHLH, higher HLA-DR+/CD38+ populations were seen in T cells, monocytes, DCs and NK cells. There was significant CD62L downregulation in neutrophils during sepsis. Our decision tree using ferritin, EGF, IL-6 and leukocytes effectively discriminated irHLH from sepsis and G3 irCRS. High CXCL-9 levels predicted the diagnosis and severity of irHLH more accurately than the conventional HScore. Conclusions: We've identified a panel of biomarkers associated with OS. CXCL9 emerges as a superior marker, outperforming HScore. The successful treatment with TCZ underscores the importance of targeted interventions. Our decision tree enhances diagnostic accuracy for sepsis-like symptoms, aiding in the differentiation between irCRS, irHLH, and sepsis. This supports the optimal implementation of personalized strategies.