Related Experiment Video

Updated: Sep 25, 2025

A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells
12:16

A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells

Published on: October 16, 2018

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Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in

Michael D Jain1, Bachisio Ziccheddu2,3, Caroline A Coughlin4,5

  • 1Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine, Tampa, FL.

Blood
|April 27, 2022
PubMed

Insights

Genomic alterations in tumors predict resistance to CD19-directed chimeric antigen receptor (CAR-19) T cell therapy for large B-cell lymphomas. Tumor-intrinsic factors, not just CD19 mutations, are key to understanding CAR-19 efficacy and resistance.

Area of Science:

  • Oncology
  • Genomics
  • Immunotherapy

Background:

  • CD19-directed chimeric antigen receptor (CAR-19) T cells represent a significant advancement in treating large B-cell lymphomas.
  • While host and tumor microenvironment factors are linked to CAR-19 efficacy and resistance, the tumor-intrinsic genomic mechanisms remain largely undefined.
  • CD19 mutations are associated with resistance but are infrequent, and most relapsed patients retain wild-type CD19, suggesting other genomic drivers of resistance.

Purpose of the Study:

  • To investigate tumor-intrinsic genomic alterations associated with resistance to CD19-directed CAR T-cell therapy in large B-cell lymphomas.
  • To identify specific genomic features that predict treatment failure in patients receiving CAR-19 therapy.

Main Methods:

  • Whole-genome sequencing was performed on 51 tumor samples from 49 patients with large B-cell lymphoma treated with CAR-19 therapy.
  • Analysis focused on identifying complex structural variants, mutational signatures (e.g., APOBEC, reactive oxygen species), and chromosomal deletions.

Main Results:

  • The presence of complex structural variants, APOBEC mutational signatures, and genomic damage from reactive oxygen species at pretreatment predicted resistance to CAR-19 therapy.
  • A recurrent deletion in the 3p21.31 chromosomal region, encompassing the RHOA tumor suppressor gene, was significantly enriched in patients who failed CAR T-cell therapy.
  • Reduced CD19 expression or monoallelic loss at pretreatment did not impact treatment responses, indicating multifaceted resistance mechanisms.

Conclusions:

  • Tumor-intrinsic genomic alterations play a critical role in the efficacy and resistance of CD19-directed CAR T-cell therapy for large B-cell lymphomas.
  • Genomic profiling, including the identification of structural variants and specific deletions like RHOA, can potentially predict CAR-19 treatment outcomes.
  • Understanding these complex genomic factors is essential for improving patient selection and developing strategies to overcome CAR-19 resistance.

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