Characterization of Leukemic Resistance to CD19-Targeted CAR T-cell Therapy through Deep Genomic Sequencing.

Autor:	Chen GM; Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, Pennsylvania., Chen CH; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Perazzelli J; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Grupp SA; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania., Barrett DM; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania., Tan K; Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, Pennsylvania.; Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2023 Jan 03; Vol. 11 (1), pp. 13-19.
DOI:	10.1158/2326-6066.CIR-22-0095
Abstrakt:	Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been a clinical breakthrough for pediatric B-cell acute lymphoblastic leukemia (B-ALL), and loss of the CD19 target antigen on leukemic cells represents a major mechanism of relapse. Previous studies have observed CD19 mutations specific to CD19- relapses, and we sought to clarify and strengthen this relationship using deep whole-exome sequencing in leukemic cells expanded in a patient-derived xenograft. By assessing pre-treatment and relapse cells from 13 patients treated with CAR T-cell therapy, 8 of whom developed CD19- relapse and 5 of whom developed CD19+ relapse, we demonstrate that relapse-specific single-nucleotide variants and small indels with high allele frequency combined with deletions in the CD19 gene in a manner specific to those patients with CD19- relapse. Before CAR T-cell infusion, one patient was found to harbor a pre-existing CD19 deletion in the context of genomic instability, which likely represented the first hit leading to the patient's subsequent CD19- relapse. Across patients, preexisting mutations and genomic instability were not significant predictors of subsequent CD19- relapse across patients, with sample size as a potential limiting factor. Together, our results clarify and strengthen the relationship between genomic events and CD19- relapse, demonstrating this intriguing mechanism of resistance to a targeted cancer immunotherapy. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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