Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia.

Abstract

Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.

• Authors: Jessica C Petrov, Masayuki Wada, Kevin G Pinz, Lulu E Yan, Kevin H Chen, Xiao Shuai, Hua Liu, Xi Chen, Lai-Han Leung, Huda Salman, Nabil Hagag, Fang Liu, Xun Jiang, Yupo Ma
• Journal: Leukemia (Leukemia) Vol. 32 Issue 6 Pg. 1317-1326 (06 2018) ISSN: 1476-5551 [Electronic] England
• PMID: 29515236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-3 Receptor alpha Subunit
• Receptors, Antigen, T-Cell
• Sialic Acid Binding Ig-like Lectin 3
• Alemtuzumab

Topics

• Alemtuzumab (therapeutic use)
• Animals
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Humans
• Immunotherapy, Adoptive (methods)
• Interleukin-3 Receptor alpha Subunit (antagonists & inhibitors)
• Leukemia, Myeloid, Acute (therapy)
• Male
• Mice
• Receptors, Antigen, T-Cell (immunology)
• Sialic Acid Binding Ig-like Lectin 3 (antagonists & inhibitors)