Toxicities of chimeric antigen receptor T cells: recognition and management

Abstract

Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy.

Figure 1

CRS toxicities by organ system. After infusion of CAR T cells, CRS toxicities affecting a wide variety of organs can occur. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 2

Response to tocilizumab in 2 patients. Patient 1 is a 54-year-old male who received T cells transduced with a CAR targeting B-cell maturation antigen. He experienced CRS starting 4 hours following T-cell infusion, with development of fevers, tachycardia, tachypnea, hypoxia, and hypotension requiring vasopressors. (A) Patient 1 received tocilizumab 25 hours after his cell infusion, which was followed by a transient decrease in temperature and heart rate. He experienced worsening CRS and received a second dose of tocilizumab on day 5 following cell infusion, which was followed by a sustained decrease in temperature and heart rate. (B) The respiratory rate of patient 1 decreased following his first dose of tocilizumab, and intubation was avoided. (C) Patient 2 is a 20-year-old woman with a history of ALL with a past history of a matched-related donor SCT. She received donor-derived T cells transduced with a CAR targeting CD19 for progressive ALL after transplant. She experienced CRS toxicity with fevers, tachycardia, tachypnea, hypoxia, left ventricular systolic dysfunction, prolonged activated PTT, and increased creatine kinase. She received tocilizumab on day 4 following CAR T-cell infusion. Her respiratory rate decreased following tocilizumab, and intubation was avoided. (D) The heart rate of patient 2 decreased following tocilizumab. (E) Following tocilizumab, CRP in patient 2 decreased over a period of days. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 3

General treatment algorithm for CRS and neurologic toxicities. A general algorithm used for treatment of CAR T-cell toxicity occurring in patients at the NCI Experimental Transplantation and Immunology Branch is shown. Professional illustration by Patrick Lane, ScEYEnce Studios.