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