Immune Effector Cell Associated Neurotoxicity (ICANS) in Pediatric and Young Adult Patients Following Chimeric Antigen Receptor (CAR) T-Cell Therapy: Can We Optimize Early Diagnosis?

Brandon Douglas Brown,Zsila Sadighi,Linda Chi,Francesco Paolo Tambaro,Kris Michael Mahadeo,Sajad Khazal,Demetrios Petropoulos,Mira Kohorst,John M Slopis,Priti Tewari

doi:10.3389/fonc.2021.634445

Abstract

The Cornell Assessment for Pediatric Delirium (CAPD) was first proposed by the Pediatric Acute Lung Injury and Sepsis Investigators Network-Stem Cell Transplantation and Cancer Immunotherapy Subgroup and MD Anderson CARTOX joint working committees, for detection of immune effector cell associated neurotoxicity (ICANS) in pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy. It was subsequently adopted by the American Society for Transplantation and Cellular Therapy. The utility of CAPD as a screening tool for early diagnosis of ICANS has not been fully characterized. We conducted a retrospective study of pediatric and young adult patients (n=15) receiving standard-of-care CAR T-cell products. Cytokine release syndrome (CRS) and ICANS occurred in 87% and 40% of patients, respectively. ICANS was associated with significantly higher peaks of serum ferritin. A change in CAPD from a prior baseline was noted in 60% of patients with ICANS, 24–72 h prior to diagnosis of ICANS. The median change from baseline to maximum CAPD score of patients who developed ICANS versus those who did not was 13 versus 3, respectively (p=0.0004). Changes in CAPD score from baseline may be the earliest indicator of ICANS among pediatric and young adult patients which may warrant closer monitoring, with more frequent CAPD assessments.

Highlights

Advances in cellular and immunotherapies such as chimeric antigen receptor (CAR) T-cells used in conjunction with lymphodepleting conditioning regimens are associated with high response rates in hematologic malignancies
The Cornell Assessment for Pediatric Delirium (CAPD) screening tool may be used in children to detect delirium, which is present in more than 25% of patients admitted to pediatric intensive care units [17,18,19]
Delirium is an acute syndrome with fluctuating awareness and cognition, and it may be an early indicator of Immune effector cell-associated neurotoxicity syndrome (ICANS)

Summary

Introduction

Advances in cellular and immunotherapies such as chimeric antigen receptor (CAR) T-cells used in conjunction with lymphodepleting conditioning regimens are associated with high response rates in hematologic malignancies. Three CAR T-cell products have been approved by the Food and Drug Administration (FDA) in the United States for the treatment of pediatric, adolescent and young adult patients with relapsed or refractory B-cell ALL and adults with large B-cell and mantle cell lymphomas. These secondgeneration CAR T-cells utilize a CD3z signaling domain with either a CD28 or 4-1BB (CD137) co-stimulatory domain to promote T-cell activation and proliferation [3]. Binding of CD19 on target tumor cells activates anti-CD19 CAR T-cells independent of major histocompatibility complex (MHC) with down-stream intracellular signaling leading to cytokine secretion, proliferation, and lytic activity [4]

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Results

Conclusion