Chimeric antigen receptor (CAR) t-cell therapy in the pediatric critical care

Abstract

In 2017, the US Food and Drug Administration (FDA) approved a form of cancer immunotherapy, specifically, a chimeric antigen receptor (CAR), for the treatment of pediatric and young adult patients with refractory CD19-positive B-cell precursor acute lymphoblastic leukemia or in second or later relapse. This autologous form CAR T-cell therapy (tisagenlecleucel) is associated with impressive response rates but is also associated with unique and potentially serious complications, namely, cytokine release syndrome (CRS) and CAR T-cell-related encephalopathy syndrome (CRES). Children who develop severe CRS and/or CRES may require critical care observation and/or rapid intervention. CAR therapy belongs to a growing class of immune effector cell (IEC) therapies which also include (i) natural killer (NK) cells with or without ex vivo activation to exert broad cytotoxicity against tumor cells, (ii) cytotoxic T lymphocytes (CTLs) expanded ex vivo against viral or tumor peptides to target infection or malignancy, (iii) regulatory T lymphocytes with or without genetic modification to induce tolerance, (iv) dendritic cells loaded with peptides or genetically engineered to express cytokines/ chemokines in order to enhance immune recognition, and (v) engineered T-cell receptors (TCRs) directed against tumor-associated antigens. Tumor flare or pseudo-progression near vital organs (which may occur in response to IEC therapies) also present important critical care considerations. CART-cell therapy carries a relatively high risk for development of CRS and/or CRES compared to other IEC therapies. Diagnostic, severity grading, and management algorithms developed for CRS and CRES should guide interdisciplinary teams caring for patients who develop these acute toxicities.