CAR T cells derived from a novel, high-affinity anti-CLL-1 monoclonal antibody exhibit a significant anti-AML effect

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cells targeting CLL-1 have demonstrated efficacy in acute myeloid leukemia (AML).
• However, the presence of CLL-1 low/negative AML cells necessitates CAR T cells with higher sensitivity for complete eradication.
• Existing anti-CLL-1 monoclonal antibodies (mAbs) may not be sufficient for all AML patient subsets.

Purpose of the Study:

• To develop novel CAR T cells with enhanced affinity and efficacy against CLL-1 positive and low/negative AML.
• To evaluate the anti-leukemic effect of CAR T cells derived from a new high-affinity anti-CLL-1 mAb (2-23) in preclinical AML models.
• To investigate the potential synergistic effect of combining 2-23 CAR T cells with menin inhibitors like revumenib.

Main Methods:

• Generation and characterization of 13 new anti-CLL-1 mAbs.
• Construction and in vitro assessment of CAR T cells derived from these mAbs, focusing on cytokine production and cytotoxicity.
• Evaluation of 2-23 CAR T cell efficacy in AML xenograft models, including survival analysis.
• In vitro assessment of revumenib's effect on CLL-1 expression and subsequent 2-23 CAR T cell-mediated cytotoxicity in specific AML subtypes.

Main Results:

• CAR T cells derived from mAb 2-23 exhibited significantly higher affinity for CLL-1 compared to the M26 mAb.
• 2-23 CAR T cells demonstrated potent cytokine production and cytotoxicity against AML cells in vitro.
• Treatment with 2-23 CAR T cells eradicated AML cells and prolonged survival in vivo xenograft models.
• Revumenib treatment increased CLL-1 expression on MLL-fusion or NPM1-mutated AML cells, enhancing their susceptibility to 2-23 CAR T cells.

Conclusions:

• Novel CAR T cells derived from the high-affinity anti-CLL-1 mAb 2-23 show significant anti-leukemic activity.
• These 2-23 CAR T cells represent a promising therapeutic strategy for CLL-1 positive AML.
• Combining 2-23 CAR T cells with revumenib may offer a new treatment option for patients with CLL-1 low/negative AML.