In severe cases CRS can be accompanied by clinical signs and laboratory abnormalities that resemble hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). In addition, patients with severe CRS frequently display vascular leakage with peripheral and pulmonary edema. Patients with severe CRS can also develop renal failure or signs of cardiac dysfunction with reduced ejection fraction on ultrasound. Of note, in patients with CRS the need for mechanical ventilation is oftentimes not due to respiratory distress but instead a consequence of the inability to protect the airway secondary to neurotoxicity. ARDS may sometimes require mechanical ventilation. Mild cases may display cough and tachypnea but can progress to acute respiratory distress syndrome (ARDS) with dyspnea, hypoxemia, and bilateral opacities on chest X-ray. Respiratory symptoms are common in patients with CRS. As in the future, T cell-engaging immunotherapeutic agents will increasingly be used outside of clinical studies and academic cancer centers it becomes paramount that oncologists and intensive care specialists are familiar with this complication and its clinical management. Thus, most of the current CRS data is derived from CAR T cell and blinatumomab studies in hematologic malignancies where CRS has been reported in frequencies of up to 100% in CD19-targeted CAR T cell trials, sometimes with fatal outcome (Table 1). blinatumomab and CD19-targeted CAR T cells revealed that CRS is the most important adverse event of these therapies. Studies of the first T cell-engaging therapies, i.e. These include dual-affinity re-targeting antibodies (DART), immune-mobilising monoclonal TCRs against cancer (ImmTAC), and other TCR-based strategies. Furthermore, there are a number of related T cell-engaging immunotherapeutic approaches in earlier clinical development. Multiple other bispecific antibody and CAR T cell constructs that target a variety of antigens are currently in clinical development. Recently, the first two CAR T cell therapies tisagenlecleucel and axicabtagene ciloleucel received FDA approval for refractory CD19-positive B-ALL and relapsed or refractory large B-cell lymphoma. In 2014, the CD19-directed CD3 BiTE blinatumomab was approved for Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL under the FDA’s accelerated approval program. Both these immunotherapeutic strategies have recently been carried forward into clinical application and have shown impressive therapeutic activity in several hematologic malignancies, such as acute lymphoblastic B cell leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and diffuse large B cell lymphoma (DLBCL). T cell-engaging immunotherapies include bispecific antibody constructs and chimeric antigen receptor (CAR) T cell therapies. Lately, with the success of the newer T cell-engaging immunotherapeutic agents there has been a growing interest in CRS since it represents one of the most frequent serious adverse effects of these therapies. Cytokine storm due to massive T cell stimulation is also a proposed pathomechanism of severe viral infections such as influenza. Furthermore, CRS was reported in the setting of haploidentical donor stem cell transplantation, and graft-versus-host disease. CRS has also been observed following administration of non-protein-based cancer drugs such as oxaliplatin and lenalidomide. Subsequently, CRS has been described after infusion of several antibody-based therapies such as anti-thymocyte globulin (ATG), the CD28 superagonist TGN1412, rituximab, obinutuzumab, alemtuzumab, brentuximab, dacetuzumab, and nivolumab. The term “cytokine release syndrome” was first coined in the early ‘90s, when the anti-T-cell antibody muromonab-CD3 (OKT3) was introduced into the clinic as an immunosuppressive treatment for solid organ transplantation. Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by a variety of factors such as infections and certain drugs.
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