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<p>Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROS<sup>low</sup> B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROS<sup>low</sup> cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月23日

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  • Pablo Domizi,
  • Jolanda Sarno,
  • Astraea Jager,
  • Milton Merchant,
  • Kaithlen Zen B. Pacheco,
  • Sean A. Yamada-Hunter,
  • Maria Caterina Rotiroti,
  • Yuxuan Liu,
  • Reema Baskar,
  • Warren D. Reynolds,
  • Brian J. Sworder,
  • Bita Sahaf,
  • Sean C. Bendall,
  • Charles G. Mullighan,
  • Ash A. Alizadeh,
  • Allison B. Leahy,
  • Regina M. Myers,
  • Bonnie Yates,
  • Hao-Wei Wang,
  • Nirali N. Shah,
  • Robbie G. Majzner,
  • Crystal L. Mackall,
  • Stephan A. Grupp,
  • David M. Barrett,
  • Elena Sotillo,
  • Kara L. Davis

摘要

Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROSlow B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROSlow cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.