Cardiovascular Complications of Chimeric Antigen Receptor T-Cell Therapy: The Cytokine Release Syndrome and Associated Arrhythmias

Abstract

In recent years, cancer treatment has evolved, and new therapies have been introduced with significant improvement in prognosis. The immunotherapies stand out owing to their efficacy and remission rate. Chimeric antigen receptor (CAR) T-cell therapy is a part of this new era of therapies. Chimeric antigen receptor T-cell therapy is a form of adoptive cellular therapy that uses a genetically encoded CAR in modified human T cells to target specific tumor antigens in a nonconventional, non-major histocompatibility complex (MHC) protein presentation. Chimeric antigen receptor T-cell therapy successfully identifies tumor antigens and through activation of T cells destroys tumoral cells. It has been found to efficiently induce remission in patients who have been previously treated for B-cell malignancies and have persistent disease. As the use of this novel therapy increases, its potential side effects also have become more evident, including major complications like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokine release syndrome is a major systemic inflammatory process as a result of massive cytokine production by the proliferating and activated CAR T cells in which multiple interleukins and immune cells contribute to the inflammatory response. Cytokine release syndrome has been associated with cardiovascular life-threatening complications including hypotension, shock, tachycardia, arrhythmias, left ventricular dysfunction, heart failure, and cardiovascular death. Arrhythmias, among its major complications, vary from asymptomatic prolonged corrected QT interval (QTc) to supraventricular tachycardia, atrial fibrillation, flutter, and ventricular arrhythmias like Torsade de pointes. This article focuses on the cardiovascular complications and arrhythmias associated with CRS and CAR T-cell therapy.

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

“…IL-6 is one of the driving pro-inflammatory cytokines that contributes to CRS and its pulmonary, cardiovascular, renal and neurologic complications [ 17 , 18 , 19 , 20 , 21 , 36 , 37 ]. Cytokine profiling in patients who developed CRS after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6, which was in agreement with our current knowledge regarding CRS that occurs in the context of BiAb therapy [ 14 , 15 , 16 , 38 , 39 , 40 ]. Within 1–2 days following the first dose of APVO436, the mean serum IL-6 concentration was elevated 145-fold over the baseline (755 vs. 5.2) and at the end of one week it was still elevated 83-fold over the baseline.…”

Cardiac toxicities in multiple myeloma: an updated and a deeper look into the effect of different medications and novel therapies

“…Chimeric Antigen Receptor T cell therapy (CAR-T), currently utilized in the treatment of R/R MM, can lead to direct and indirect cardiac toxicities, mainly through the associated cytokine release syndrome (CRS), where the increase in several inflammatory markers and cytokines can lead to hypotension, tachycardia/arrhythmias partly related to the activation of the sympathetic nervous system leading to cardiac stimulation, in addition to VD related to possible myocyte shortening and mitochondrial dysfunction [ 43 ]. No cardiac failure was reported with Idecabtagene vicleucel in the KarMMa trial [ 44 ].…”

Overview of Adverse Events Associated With Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

“…The most common abnormalities found in these patients are asymptomatic prolonged QTc interval and atrial fibrillation. Hypotension has been reported in up to one-third of patients with CRS [75]. The other reported cardiac toxicities include an increase in serum troponins and a decrease in left ventricular systolic function.…”

“…The other reported cardiac toxicities include an increase in serum troponins and a decrease in left ventricular systolic function. The resulting ventricular dysfunction may be related to a release of tumour necrosis factor-a, which may decrease myocyte shortening and mitochondrial dysfunction [75]. CAR T-cell therapy can be used to achieve remission before allogeneic stem cell transplant; therefore, the reversibility of end-organ toxicities is very important [68].…”