CD33-CD123 IF-THEN Gating Reduces Toxicity while Enhancing the Specificity and Memory Phenotype of AML-Targeting CAR-T Cells

Blood Cancer Discov. 2025 Jan 8;6(1):55-72. doi: 10.1158/2643-3230.BCD-23-0258.

Abstract

Our study demonstrates the use of "IF-THEN" SynNotch-gated CAR-T cells targeting CD33 and CD123 in AML reduces off-tumor toxicity. This strategy enhances T-cell phenotype, improves expansion, preserves HSPCs, and mitigates cytokine release syndrome-addressing critical limitations of existing AML CAR-T therapies.

MeSH terms

  • Animals
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Interleukin-3 Receptor alpha Subunit* / metabolism
  • Leukemia, Myeloid, Acute* / immunology
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / therapy
  • Phenotype
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • Receptors, Chimeric Antigen* / metabolism
  • Sialic Acid Binding Ig-like Lectin 3* / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Sialic Acid Binding Ig-like Lectin 3
  • Interleukin-3 Receptor alpha Subunit
  • CD33 protein, human
  • Receptors, Chimeric Antigen
  • IL3RA protein, human