2025 PACUPrep BCCCP Preparatory Course Biologic Immunotherapies & Cytokine Release Syndrome Fundamentals of Biologic Immunotherapies & CRS: Epidemiology, Pathophysiology, and Risk Factors
Biologic Immunotherapies & Cytokine Release Syndrome

Fundamentals of Biologic Immunotherapies & Cytokine Release Syndrome

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Lesson Objective

Describe the foundational principles of biologic immunotherapies and cytokine release syndrome (CRS), including epidemiology, immunopathogenesis, and risk factors.

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.
Pearl IconA shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Unifying Trigger Expand/Collapse Icon

T-cell activation is the unifying trigger for CRS across these diverse biologic agents. Furthermore, combination checkpoint blockade may increase CRS risk through synergistic immune activation, highlighting the dose-dependent nature of this toxicity.

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.

Table 1. CRS Incidence by Agent and Indication
Agent Indication CRS Incidence Severe CRS Rate (Grade ≥3)
Axicabtagene ciloleucel (CAR-T) Refractory large B-cell lymphoma 58–93% 13–28%
Tisagenlecleucel (CAR-T) Pediatric/young adult ALL ~77% ~46%
Blinatumomab (BiTE) Relapsed ALL 14–50% 5–10%
Pembrolizumab + Ipilimumab Melanoma <1% Rare
Pearl IconA shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Tumor Burden Expand/Collapse Icon

A high tumor burden is a major risk factor that correlates with both earlier onset and more severe CRS. This is because the increased antigen density drives more robust T-cell expansion and a greater initial release of inflammatory cytokines.

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.

Pathophysiology of Cytokine Release Syndrome A flowchart showing the CRS cascade. A CAR-T cell binds to a tumor cell, releasing IFN-gamma and TNF-alpha. These cytokines activate a macrophage, which in turn releases IL-6 and IL-1. IL-6 causes endothelial dysfunction leading to capillary leak and neurotoxicity. IL-1 contributes to fever and systemic inflammation. Tocilizumab is shown blocking IL-6, and Anakinra is shown blocking IL-1. CAR-T Cell (or BiTE-engaged T-cell) Tumor Cell Macrophage Endothelial Cell IFN-γ TNF-α IL-6 IL-1 Capillary Leak Hypotension Neurotoxicity Systemic Inflammation Tocilizumab 🚫 Anakinra
Figure 1: The CRS Pathophysiologic Cascade. Antigen binding by T-cells or CAR-T cells triggers release of IFN-γ and TNF-α, which activate myeloid cells (macrophages). These cells amplify the response by producing large amounts of IL-6 and IL-1, key drivers of endothelial dysfunction, systemic inflammation, and end-organ toxicity.
Pearl IconA shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Therapeutic Targets Expand/Collapse Icon

IL-6 blockade with tocilizumab targets a pivotal node in the CRS cascade and is the first-line therapy for moderate to severe CRS. In cases refractory to IL-6 blockade, macrophage-derived IL-1 is an important contributor to severity; anakinra (an IL-1 receptor antagonist) is an emerging and effective adjunct therapy.

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.
Pearl IconA shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Pre-Therapy Cardiac Assessment Expand/Collapse Icon

Pre-CAR-T echocardiography and baseline cardiac biomarkers (e.g., troponin, NT-proBNP) are crucial for unmasking subclinical cardiac dysfunction. These findings can help identify patients who may benefit from prophylactic measures or more intensive monitoring during therapy.

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.
Pearl IconA shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Rapid Access Protocols Expand/Collapse Icon

Implementing rapid tocilizumab delivery protocols, such as ensuring on-site stocking in pharmacies and ICUs and using standing order sets, can dramatically reduce the time to intervention. This proactive approach has been shown to mitigate CRS severity and improve patient outcomes.

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.
Controversy IconA chat bubble with a question mark, indicating a point of controversy or debate. Controversy: Prophylactic vs. Reactive Tocilizumab Expand/Collapse Icon

The optimal timing of tocilizumab is debated. Prophylactic administration in high-risk patients may prevent severe CRS but raises concerns about potentially blunting the antitumor efficacy of the immunotherapy. Reactive therapy, given at the first sign of CRS, is the current standard but may not prevent progression in all patients. Clinical trials are ongoing to resolve this question.

References

  1. Giavridis T, van der Stegen SJC, Eyquem J, et al. CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24(6):731–738.
  2. Gust J, Hay KA, Hanafi L-A, et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–1419.
  3. Hay KA, Hanafi L-A, Li D, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–2306.
  4. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–638.
  5. Leclercq-Cohen G, Steinhoff N, Alberti Servera L, et al. Dissecting the mechanisms underlying the cytokine release syndrome (CRS) mediated by T-cell bispecific antibodies. Clin Cancer Res. 2023;29(14):4449–4463.
  6. Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22(2):85–96.
  7. Maus MV, Alexander S, Bishop MR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. J Immunother Cancer. 2020;8:e001511.
  8. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544.
  9. Radtke KK, Bender BC, Li Z, et al. Clinical pharmacology of cytokine release syndrome with T-cell-engaging bispecific antibodies: current insights and drug development strategies. Clin Cancer Res. 2025;31(2):245–257.
  10. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6:56.
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