Hyperleukocytosis in a Neuroblastoma Patient After Treatment With Natural Killer T Cells Expressing a GD2-Specific Chimeric Antigen Receptor and IL-15

Authors

Gengwen Tian
Amy N Courtney
Hangjin Yu
Saleh Bhar
Xin Xu
Gabriel A Barragán
Claudia Martinez Amador
Nisha Ghatwai
Michael S Wood
Deborah Schady
Antonino Montalbano
Shantan Reddy
Aoife M Roche
David de la Cerda
Donald Williams Parsons
Erica J Di Pierro
Frederic D Bushman
Andras Heczey
Leonid S Metelitsa

Publication Date

1-11-2025

Journal

The Journal for ImmunoTherapy of Cancer

DOI

10.1136/jitc-2024-010156

PMID

39800376

PMCID

PMC11883886

PubMedCentral® Posted Date

1-11-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Gangliosides, Immunotherapy, Adoptive, Interleukin-15, Natural Killer T-Cells, Neuroblastoma, Receptors, Chimeric Antigen, Clinical Trials, Phase I as Topic

Abstract

The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). 12 previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. We report that the use of aAPCs instead of PBMCs for CAR-NKT restimulation contributed to a hyperproliferative state associated with distinct gene expression that possibly led to explosive lymphocyte expansion and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products, especially those armed with transgenic cytokines.