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IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies

Pablo Domizi1, Jolanda Sarno2,3,4, Astraea Jager2

  • 1Department of Pediatrics, Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA. domizi@stanford.edu.

Nature Communications
|April 23, 2025
PubMed

Insights

Low IKAROS levels in B-cell acute lymphoblastic leukemia (B-ALL) cells drive antigen escape during chimeric antigen receptor (CAR) T-cell therapy. This discovery identifies IKAROS as a potential prognostic target to prevent relapse.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Antigen escape relapse poses a significant challenge in chimeric antigen receptor (CAR) T-cell immunotherapies for B-cell acute lymphoblastic leukemia (B-ALL).
  • Identifying tumor-intrinsic factors that contribute to antigen loss is crucial for improving therapeutic outcomes.

Purpose of the Study:

  • To investigate tumor-intrinsic factors driving antigen loss in B-ALL following CAR T-cell treatment.
  • To understand the role of IKAROS in regulating the expression of CD19 and CD22 antigens targeted by immunotherapies.

Main Methods:

  • Single-cell analyses were performed on 61 B-ALL patient samples treated with CAR T cells.
  • Epigenetic and transcriptional changes in IKAROS-low B-ALL cells were analyzed.
  • CD19 and CD22 surface expression levels were assessed in relation to IKAROS levels.

Main Results:

  • Low IKAROS levels in pro-B-like B-ALL cells before treatment correlated with antigen escape.
  • IKAROS-low B-ALL cells exhibited epigenetic and transcriptional alterations, resembling progenitor cells and leading to reduced CD19/CD22 expression.
  • CD19 and CD22 expression was found to be IKAROS dose-dependent and reversible.
  • IKAROS-low cells demonstrated increased resistance to CD19- and CD22-targeted therapies.

Conclusions:

  • IKAROS plays a critical role in regulating the expression of CD19 and CD22, antigens targeted by widely used immunotherapies.
  • IKAROS levels are a potential prognostic marker for antigen escape relapse in B-ALL patients undergoing CAR T-cell therapy.
  • Targeting IKAROS could offer a strategy to overcome antigen escape and improve treatment efficacy.

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