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. 2019 Dec 12;134(24):2149-2158.
doi: 10.1182/blood.2019001463.

Preemptive Mitigation of CD19 CAR T-cell Cytokine Release Syndrome Without Attenuation of Antileukemic Efficacy

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Preemptive Mitigation of CD19 CAR T-cell Cytokine Release Syndrome Without Attenuation of Antileukemic Efficacy

Rebecca A Gardner et al. Blood. .
Free PMC article

Abstract

Immunotherapy with the adoptive transfer of T cells redirected with CD19-specific chimeric antigen receptors (CARs) for B-lineage acute lymphoblastic leukemia (ALL) can salvage >80% of patients having relapsed/refractory disease. The therapeutic index of this emerging modality is attenuated by the occurrence of immunologic toxicity syndromes that occur upon CAR T-cell engraftment. Here, we report on the low incidence of severe cytokine release syndrome (CRS) in a subject treated with a CAR T-cell product composed of a defined ratio CD4:CD8 T-cell composition with a 4-1BB:zeta CAR targeting CD19 who also recieved early intervention treatment. We report that early intervention with tocilizumab and/or corticosteroids may reduce the frequency at which subjects transition from mild CRS to severe CRS. Although early intervention doubled the numbers of subjects dosed with tocilizumab and/or corticosteroids, there was no apparent detrimental effect on minimal residual disease-negative complete remission rates or subsequent persistence of functional CAR T cells compared with subjects who did not receive intervention. Moreover, early intervention therapy did not increase the proportion of subjects who experience neurotoxicity or place subjects at risk for infectious sequelae. These data support the contention that early intervention with tocilizumab and/or corticosteroids in subjects with early signs of CRS is without negative impact on the antitumor potency of CD19 CAR T cells. This intervention serves to enhance the therapeutic index in relapsed/refractory patients and provides the rationale to apply CAR T-cell therapy more broadly in ALL therapy. This trial was registered at www.clinicaltrials.gov as #NCT020284.

Conflict of interest statement

Conflict-of-interest disclosure: T.M.C. has a family member who is an employee of and has an equity interest in Juno Therapeutics, Inc., a Celgene company. D.H.L. is an employee of and has an equity interest in Juno Therapeutics, Inc., a Celgene company. M.C.J. has received consulting fees and grants from and is an inventor on patents licensed to Juno Therapeutics, Inc., a Celgene company. Seattle Children’s Hospital received funds from Juno Therapeutics, Inc., a Celgene company. The remaining authors declare no competing financial interests.

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