Distinct immune signatures are a potent tool in the clinical management of cytokine-related syndrome during immune checkpoint therapy

Immune-related cytokine release syndrome (irCRS) frequently occurs during immune checkpoint inhibitor (ICI) therapy. In the present study, we have attempted to identify biomarkers in oncology patients experiencing irCRS-like symptoms (n=35), including 9 patients with hemophagocytic lymphohistiocytosis (irHLH)-like manifestations (8 classified as Grade (G) 4 irCRS and 1 as G3 irCRS) and 8 with sepsis, differentiating between irCRS, irHLH and sepsis. Patients grouped in three clusters based on distinct cytokine profiles and survival outcomes. We identified 24 biomarkers that significantly discriminated between irHLH and irCRS G3 (P < 0.0455 to < 0.0027). Notably, HGF and ferritin demonstrated superior predictive values over the traditional HScore, with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. Furthermore, CXCL9 not only distinguished between irHLH and irCRS G3, but was also a predictor of treatment intensification with tocilizumab (TCZ) with a PPV of 90% and a NPV of 100%. Other parameters, such as leukocyte count, neutrophils, ferritin, IL-6, IL-7, EGF, fibrinogen, and GM-CSF, were effective in discriminating sepsis from high-grade irCRS with a PPV of 75-80% and an NPV of 100%. In comparison to sepsis, the frequencies of CXCR5+ or CCR4+ CD8 memory, CD38+ ITM monocytes, and CD62L+ neutrophils were observed to be higher in high-Grade irCRS. Of note, TCZ treatment led to complete resolution of clinical symptoms in 12 patients with high-grade irCRS refractory to corticosteroids (CS). These findings demonstrate the power of unique immunologic biomarkers in determining the severity of irCRS, in predicting survival, and distinguishing between high-grade irCRS, irHLH and sepsis. Therefore, these distinct unique signatures are instrumental for the optimal development of personalized clinical and therapeutic management in patients experiencing irCRS patient. ### Competing Interest Statement MO received honoraria and speaker fees from Moderna, Roche and BMS. ### Funding Statement The study was funded by CHUV institutional funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Canton of Vaud (Commission cantonal d'ethique de la recherche sur l'etre humain (CER-VD)) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets supporting the results of this study are not publicly available. Requests for access to the dataset will be granted upon reasonable request to the principal investigator. Study data will be managed, stored, shared, and archived according to CHUV standard operating procedures to ensure the continued quality, integrity, and utility of the data.