1. Overview of Biologic Immunotherapies and CRS

Biologic immunotherapies harness targeted immune mechanisms—including monoclonal antibodies, checkpoint inhibitors, and CAR-T cells—to treat a growing number of malignancies and autoimmune diseases. Cytokine Release Syndrome (CRS) represents a shared, on-target toxicity driven by excessive immune activation that can lead to life-threatening organ dysfunction.

A. Definitions & Classification

• Monoclonal antibodies (mAbs): These are engineered immunoglobulins designed to bind specific antigens. Their mechanisms include antibody-dependent cell-mediated cytotoxicity (ADCC), complement activation, and receptor blockade.
• Checkpoint inhibitors: These are antibodies, such as anti–PD-1 and anti–CTLA-4, that relieve inhibitory signals on T cells, thereby enhancing antitumor immune responses.
• CAR-T therapies: This advanced therapy involves modifying a patient’s own T cells with chimeric antigen receptors (CARs), enabling them to target and destroy tumor cells in a manner independent of the major histocompatibility complex (MHC).

B. Indications & Clinical Contexts

• mAbs: Examples include rituximab for B-cell lymphomas and TNF inhibitors for rheumatologic conditions.
• Checkpoint inhibitors: Widely used in melanoma, non–small cell lung cancer, and Hodgkin lymphoma.
• CAR-T: CD19-targeted products (e.g., axicabtagene ciloleucel, tisagenlecleucel) are used in refractory B-cell malignancies, while BCMA-directed therapies are used in multiple myeloma.

2. Epidemiology & Incidence of CRS

The incidence of CRS varies dramatically by the specific agent, its indication, and the dosing strategy employed. It ranges from being a rare event with single-agent checkpoint inhibitors to a near-universal occurrence with certain CAR-T products.

• CAR-T therapies (CD19-directed): CRS occurs in 58–93% of patients, with severe (grade ≥3) CRS in 13–28%.
• Bispecific T-cell engagers (BiTEs): Agents like blinatumomab cause CRS in 14–50% of cases, though it is usually lower-grade.
• Checkpoint inhibitors: CRS is rare (<1%), primarily seen in combination regimens.

Strategies like step-up dosing protocols can attenuate the initial cytokine peak by allowing for gradual antigen exposure, which may delay the onset and reduce the severity of CRS. Despite the adoption of standardized ASTCT grading, real-world data suggest underreporting of low-grade CRS and significant intercenter variability in management.

3. Pathophysiology of CRS

CRS arises from a self-amplifying cytokine cascade initiated by T-cell or CAR-T activation. This initial trigger is propagated by innate immune cells, particularly monocytes and macrophages, leading to systemic inflammation, vascular leak, and multi-organ dysfunction.

4. Influence of Chronic Comorbidities on CRS

Baseline organ dysfunction and pre-existing immune activation can significantly modulate CRS risk by altering cytokine clearance, hemodynamic reserve, and inflammatory thresholds.

• Cardiovascular disease: Reduced hemodynamic reserve can lead to early and profound vasopressor-dependent hypotension. Invasive hemodynamic monitoring should be considered for high-risk patients.
• Renal impairment: Decreased cytokine clearance prolongs exposure to inflammatory mediators. Fluid management and drug dosing must be carefully adjusted.
• Hepatic impairment: An impaired acute-phase protein response and altered drug metabolism can complicate the use of immunomodulatory agents.
• Autoimmune/inflammatory disorders: Elevated baseline cytokine levels may potentiate the CRS cascade, requiring an individualized risk–benefit assessment.

5. Social Determinants of Health in CRS

Socioeconomic factors, including access to care, health literacy, and system-level barriers, can significantly impact the timely recognition and management of CRS, thereby influencing morbidity and mortality.

• Medication access: Formulary restrictions, prior authorization requirements, or institutional shortages can delay the administration of critical therapies like tocilizumab and corticosteroids.
• Health literacy: Patients and their caregivers may fail to recognize and report early signs of CRS (e.g., fever, malaise, confusion), delaying intervention.
• Geographic barriers: Community or rural centers may lack 24/7 on-site expertise in managing severe CRS. Hub-and-spoke telehealth models and clear transfer protocols can help bridge these gaps.

6. Risk Stratification & Predictive Models

Integrating clinical, biomarker, and pharmacologic data allows for the early identification of patients at high risk for developing severe CRS. This enables proactive monitoring and preemptive interventions.

• Clinical Predictors: Key factors include high tumor burden, the intensity of the lymphodepleting chemotherapy regimen, and specific CAR-T construct features (e.g., a CD28 costimulatory domain).
• Biomarkers: Early and rapid rises in inflammatory markers are highly predictive. A C-reactive protein (CRP) level >100 mg/L and a ferritin level >10,000 ng/mL within 48 hours post-infusion can predict subsequent grade ≥3 CRS with over 80% specificity.
• Timing of Assessment: Risk assessment is a dynamic process that should be performed pre-therapy, immediately after lymphodepletion, and during the early post-infusion period (days 1–2) when CRS typically emerges.