What is the pathophysiology of cytokine release syndrome in haploidentical (human leukocyte antigen-mismatched) CAR-T (Chimeric Antigen Receptor T-cell) therapy?

From the Guidelines

Cytokine release syndrome (CRS) in haploidentical CAR-T therapy should be managed with tocilizumab as the first-line therapy, followed by corticosteroids for refractory cases, and supportive care to mitigate the risk of morbidity, mortality, and poor quality of life. The pathophysiology of CRS involves the rapid activation and proliferation of engineered T cells, triggering an excessive inflammatory response characterized by the release of cytokines like interferon-gamma, TNF-alpha, and IL-6 1. This process can lead to endothelial activation, capillary leak, hypotension, and potential multi-organ dysfunction. In haploidentical settings, the risk of CRS may be heightened due to potential HLA disparities triggering additional immune responses.

Key Considerations

• The incidence of CRS can vary depending on the CAR-T product, disease characteristics, and CRS grading system, with grade 3 CRS reported in 10%-30% of patients 1.
• Management of CRS includes close monitoring with frequent vital signs and laboratory assessments, grading CRS severity (mild to severe), and implementing a stepwise treatment approach.
• Tocilizumab, an IL-6 receptor antagonist, is the first-line therapy at 8 mg/kg IV (maximum 800 mg), with potential for a second dose if symptoms persist after 8-12 hours 1.
• For refractory cases or severe neurological symptoms, corticosteroids like dexamethasone (10 mg IV every 6 hours) or methylprednisolone (1-2 mg/kg/day) are added 1.
• Supportive care includes IV fluids, vasopressors for hypotension, oxygen supplementation, and antipyretics for fever management.

Additional Considerations

• Hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (HLH/MAS) can occur in patients treated with CAR T-cell therapy, with an estimated incidence of 3.5% 1.
• Clinical management of HLH/MAS mirrors the strategies used for managing CRS, which consists of anti-IL-6 therapy and aggressive use of corticosteroids.
• Prompt treatment is required for HLH/MAS, and some cases may require additional therapies such as anakinra or etoposide.

From the FDA Drug Label

The efficacy of ACTEMRA for the treatment of CRS was assessed in a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematological malignancies Evaluable patients had been treated with tocilizumab 8 mg/kg (12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. Thirty-one patients (69%; 95% CI: 53%–82%) achieved a response Achievement of resolution of CRS within 14 days was confirmed in a second study using an independent cohort that included 15 patients (range: 9–75 years old) with CAR T cell-induced CRS.

Cytokine Release Syndrome (CRS) treatment with Tocilizumab:

• The FDA drug label indicates that Tocilizumab is effective in treating CRS, with a response rate of 69% in patients with CAR T-cell induced CRS.
• The recommended dose for CRS treatment is 8 mg/kg (12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids.
• Resolution of CRS was achieved within 14 days in the majority of patients 2.

From the Research

Pathophysiology of Cytokine Release Syndrome

• Cytokine release syndrome (CRS) is a severe toxicity associated with chimeric antigen receptor (CAR) T-cell therapy, characterized by fever, hypotension, and respiratory insufficiency 3.
• The severity of CRS is mediated by interleukin-6 (IL-6), IL-1, and nitric oxide (NO) produced by recipient macrophages, rather than CAR T cell-derived cytokines 3.
• Elevated levels of IL-6 serve as a driver for host immune dysregulation, similar to macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) 4.

Treatment of Cytokine Release Syndrome

• Tocilizumab, an IL-6 receptor antibody, has been approved for the treatment of severe or life-threatening CAR T cell-induced CRS in adults and pediatric patients 2 years of age and older 5.
• The efficacy of tocilizumab in treating CRS has been demonstrated in several studies, with response rates ranging from 53% to 69% 5, 4.
• The optimal dose and schedule of tocilizumab for treatment of CAR T cell-induced CRS are still being investigated, and further research is needed to determine the best approach 5, 4.

Haploidentical CAR-T Cell Therapy and Cytokine Release Syndrome

• There is limited information available on the specific relationship between haploidentical CAR-T cell therapy and cytokine release syndrome.
• However, it is known that CAR T cell-induced CRS can occur with various CAR constructs, and tocilizumab has been used to treat CRS in these cases 4.
• Severe CRS has been associated with hematologic toxicity following CD19 CAR T-cell therapy, including impaired hematopoietic recovery and high-grade cytopenias 6.

Management of Cytokine Release Syndrome

• Prompt identification and management of CRS are crucial to prevent life-threatening complications 7.
• The use of tocilizumab, as well as other therapies such as corticosteroids, may be considered for the treatment of CAR T cell-induced CRS 5, 7.
• Alternative therapies, such as IL-1 blockade, may also be explored for the treatment of refractory CRS 3.