The advent of immune checkpoint inhibitors (ICIs) has marked a pivotal turning point in the landscape of cancer treatment, with their remarkable efficacy across a spectrum of malignancies. However, they are frequently associated with immune-related adverse events (irAEs), which encompass a range of immune-mediated toxicities that raise substantial clinical challenges. Among these, immune-related cytokine release syndrome (irCRS) can be severe and life-threatening. IrCRS is characterized by an acute systemic inflammatory response due to excessive cytokine release. While the occurrence of cytokine release syndrome in patients undergoing ICIs is relatively low (1%-6%), severe cases (grade 3 or 4) are observed in nearly 1%-2% of patients.

Historically, irCRS has been associated with monoclonal antibodies and T-cell-engaging therapies, such as CAR T-cell treatments. However, it is now increasingly observed with ICI therapy. Severe irCRS has the potential to result in multiorgan dysfunction and, in some cases, fatal outcomes. The clinical features of this condition frequently overlap with those of infectious diseases. In severe cases, irCRS may present with sepsis-like clinical signs and laboratory changes mimicking sepsis, macrophage activation syndrome (MAS), or immune-related hemophagocytic lymphohistiocytosis (irHLH). A subgroup of patients treated with CAR T cells or BITE can develop HLH-like features as a severe variant of cytokine release syndrome. In addition, CAR T-cell-associated HLH (IEC-HS) identified as a CRS variant presented cytokine profiles and clinical manifestations like secondary HLH/(MAS) and is likely to be a distinct entity from irHLH. Hemophagocytic lymphohistiocytosis (HLH) can present with a wide spectrum of manifestations ranging from isolated biological abnormalities to a severe multiorgan clinical syndrome. Distinguishing between irCRS, especially in high-grade15 irHLH, and sepsis in patients receiving ICI therapy is crucial for effective clinical management.

A significant gap exists in the current understanding of the progression of irCRS and its potential evolution into or coexistence with a compensatory anti-inflammatory response syndrome (irCARS), which was identified in sepsis conditions through the implication of two main anti-inflammatory cytokines, namely interleukin (IL)-10 and IL1RA.

An understanding of this balance between pro- and anti-inflammatory responses is essential for the optimization of patient management and treatment outcomes. Furthermore, the potential for high-grade irCRS to manifest with HLH-like symptoms introduces additional complexity to the diagnostic process, underscoring the need for more nuanced therapeutic approaches. Delineation of this possible common inflammatory continuum and its potential overlap with HLH-like presentations is essential to optimize therapeutic strategies and clinical outcomes.

A variety of grading systems for cytokine release syndrome (CRS) have been proposed with the objective of establishing standardized criteria. The current grading systems for cytokine release syndrome with the diversity of criteria used may represent limitations and may not fully capture the nuances of irCRS. For instance, the HScore, which is typically employed for reactive HLH risk assessment, may not be wholly suitable for irHLH cases associated with ICIs. The incorporation of precise immunological measurements into these grading systems has the potential to enhance severity assessment and prognostic predictions, which could ultimately facilitate more effective patient management.

A pilot study has investigated whether immunologic biomarkers could contribute to enhancing the current grading systems by providing clinicians with more tools to assess the severity of irCRS accurately through the integration of additional validated biomarkers. For these purposes, a comprehensive set of 115 biomarkers, including 50 cytokines, chemokines, and growth factors and 44 cellular markers, were analyzed to capture a comprehensive immunological profile. The ultimate goal was to identify a minimal set of key biomarkers that could distinguish between different clinical manifestations of irCRS, including irHLH and sepsis, predict severity, and inform the development of tailored treatment approaches based on specific immunological profiles. These approaches could be implemented in routine clinical settings without the need for specialized resources. Moreover, the potential use of Tocilizumab for refractory corticosteroid (CS)-irCRS was investigated. It is anticipated that these findings will facilitate the development of personalized therapeutic interventions.

Twenty-four biomarkers significantly distinguished between immune-related hemophagocytic lymphohistiocytosis 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 immune-related hemophagocytic lymphohistiocytosis from grade 3 irCRS and predicted the need for Tocilizumab 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 immune-related cytokine release syndrome (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 immune-related cytokine release syndrome compared with sepsis.

All 12 patients with high-grade immune-related cytokine release syndrome refractory to corticosteroid treated with Tocilizumab experienced complete resolution.

In conclusion, this study highlights the importance of specific immunologic biomarkers in determining immune-related cytokine release syndrome severity, predicting outcomes, and distinguishing between immune-related hemophagocytic lymphohistiocytosis, immune-related cytokine release syndrome, and sepsis. It has also demonstrated the efficacy of Tocilizumab in managing high-grade immune-related cytokine release syndrome, underscoring the need for personalized therapeutic strategies based on these biomarkers. ( Xagena_2025 )

Daoudlarian D et al, Ann Oncol 2025;36(4):444-459

XagenaMedicine_2025