General review
Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy

https://doi.org/10.1016/j.retram.2018.03.003Get rights and content

Abstract

T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR-T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CD19-specific CAR-T cell therapy can be offset by significant toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. In this report of our presentation at the 2018 Second French International Symposium on CAR-T cells (CAR-T day), we describe the clinical presentations of CRS and neurotoxicity in a cohort of 133 adults treated with CD19 CAR-T cells at the Fred Hutchinson Cancer Research Center, and provide insights into the mechanisms contributing to these toxicities.

Introduction

T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR-T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CAR T-cell therapy can be offset by toxicities, such as cytokine release syndrome (CRS) and neurotoxicity, which could hamper its widespread clinical application.

Section snippets

Efficacy of CD19 CAR-T cell therapy

CAR-T cell therapy has shown remarkable efficacy in patients with R/R CD19+ hematologic malignancies. In R/R ALL, we [1] and others [2], [3], [4], [5], [6], [7] have reported minimal residual disease (MRD)-negative complete remission (CR) rates ranging from 60% [5] to 93% [1]. In R/R non-Hodgkin lymphoma (NHL), CAR T-cell therapy achieved best overall response rates (ORR) of 53–82% [8], [9], [10], [11], [12]; in R/R CLL patients, we [13] and others [14] have reported ORR of 74% and 57%,

CRS and neurotoxicity: clinical presentation and incidence

Upon recognition of CD19-expressing cells (normal B-cells or CD19+ tumor cells) CD19 CAR-T cells proliferate, exert cytotoxic effects against their target cells, and release cytokines that may trigger a systemic inflammatory response. This is thought to initiate CRS, which is characterized clinically by a variety of systemic symptoms and signs, such as fever, hypotension, capillary leak, coagulopathy and occasionally multiorgan failure. The presentation of CRS may differ between distinct CAR-T

The FHCRC experience

Recently, we reported a clinical and biological description of CRS [16] and neurotoxicity [17] in 133 patients who underwent CD19 CAR T-cell therapy at our institution to treat ALL, NHL or CLL. The patients received cyclophosphamide +/− fludarabine-based lymphodepletion followed by the infusion of CD19 CAR-T cells formulated in a defined 1:1 ratio of CD4+:CD8+ CAR-T cells. CRS with fever preceded neurotoxicity in a majority of cases. The severity of neurotoxicity was associated with the

Pathogenesis of CRS and neurotoxicity

The pathogenesis of CRS and neurotoxicity is incompletely understood. Analysis of patients treated in our study provided insights into the mechanisms contributing to these toxicities [16], [17]. The presence of hypotension, capillary leak, and a consumptive coagulopathy suggested that endothelial dysfunction might be present in severe CRS and/or neurotoxicity. We examined serum angiopoietin-2 and -1 and von Willebrand factor (VWF) concentrations in patients after CAR-T cell infusion and found

Conclusions

CRS and neurotoxicity after CD19 CAR-T cell therapy are usually of mild-moderate severity and reversible. However, some patients develop severe toxicity associated with robust CAR-T cell expansion and high cytokine concentrations in serum. The finding of endothelial activation in these patients may open new avenues to treat or prevent CAR-T cell associated CRS and/or neurotoxicity.

Disclosure of interest

CT: Juno Therapeutics, Seattle Genetics, Precision Biosciences, Adaptive Biotechnologies, Bluebird Bio, Celgene, Gilead Sciences (Consulting or Advisory Role); Juno Therapeutics (Research Funding). JG: Juno Therapeutics (Research Funding).

Acknowledgements

We thank the FHCRC Cell Processing Facility and Seattle Cancer Care Alliance (SCCA) Cell Therapy Laboratory, and the staff of the Program in Immunology and SCCA Immunotherapy Clinic. Funding for this study was provided by: NCI R01 CA136551; NIDDK P30 DK56465; NCI P30 CA15704; Life Science Discovery Fund; Bezos Family Foundation; Juno Therapeutics, Inc; University of British Columbia Clinical Investigator Program.

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