Cytokine Release Syndrome (CRS)

CRS can lead to overwhelming systemic inflammation, hemodynamic instability,
multiple organ dysfunction, and potentially death.

Cytokine release syndrome (CRS) is a systemic inflammatory response with outpouring of the inflammatory cytokines due to stimulus triggered by a variety of factors such as infections, immunotherapy, especially those involving T-cell engagers, and antibody-based therapies. Cytokines are signaling molecules that can mediate and regulate the human body’s immune response and inflammation, which is protective in nature under normal circumstances. However, when the levels of cytokine are too high, which overly stimulates the immune response, healthy cells are destroyed and essential organs are damaged. CRS can be present with a variety of symptoms ranging from flu-like symptoms to severe multi-organ system failure or even death. Mild symptoms of CRS include fever, fatigue, headache, rash etc. while more severe symptoms include high fever, hypotension, vascular leakage, acute respiratory distress, organ failure etc. Patients at high risk for severe CRS include those with large tumor burdens, with comorbidities, and who develop early onset CRS within 3 days of infusion, although occasionally severe CRS can occur outside of these parameters.

Cytokine release syndrome is a the most common complication of CAR-T therapy. The CRS rates of any grade range from 37% to 93% for patients with lymphoma and 77% to 93% for those with leukemia. For CRS up to grade 3, the rates are 1%–23% for patients with lymphoma and 23%–46% for patients with acute lymphoblastic leukemia. Approximately 45%–50% of patients enrolled in the early CAR T-cell trials required intensive care management.

Current treatment for CRS is limited to supportive care. In serious cases, monoclonal antibodies are used used. Most of the monoclonal antibodies target cytokine IL-6. Corticosteroids are often promptly administered if the patient does not have a rapid response to IL-6 receptor blockade. However, as steroids suppress the immune system, which can reduce the effectiveness the CAR-T Therapy, the treatment period needs to be kept as short as possible to minimize the detrimental effects on the effectiveness of immunotherapy. Macrophage-Nanosponge have demonstrated the ability to neutralize a wide range of elevated cytokines, not limited to IL-6, without compromising the immune system and reducing the effectiveness of immunotherapy. As a result, it is a promising treatment option for patients suffering from CRS.