Abstract
Background aims
Efforts to safely and effectively treat acute myeloid leukemia (AML) by targeting
a single leukemia-associated antigen with chimeric antigen receptor (CAR) T cells
have met with limited success, due in part to heterogeneous expression of myeloid
antigens. The authors hypothesized that T cells expressing CARs directed toward two
different AML-associated antigens would eradicate tumors and prevent relapse.
Methods
For co-transduction with the authors’ previously optimized CLL-1 CAR currently in
clinical study (NCT04219163), the authors generated two CARs targeting either CD123
or CD33. The authors then tested the anti-tumor activity of T cells expressing each
of the three CARs either alone or after co-transduction. The authors analyzed CAR
T-cell phenotype, expansion and transduction efficacy and assessed function by in vitro and in vivo activity against AML cell lines expressing high (MOLM-13: CD123 high, CD33 high,
CLL-1 intermediate), intermediate (HL-60: CD123 low, CD33 intermediate, CLL-1 intermediate/high)
or low (KG-1a: CD123 low, CD33 low, CLL-1 low) levels of the target antigens.
Results
The in vitro benefit of dual expression was most evident when the target cell line expressed low
antigen levels (KG-1a). Mechanistically, dual expression was associated with higher
pCD3z levels in T cells compared with single CAR T cells on exposure to KG-1a (P < 0.0001). In vivo, combinatorial targeting with CD123 or CD33 and CLL-1 CAR T cells improved tumor
control and animal survival for all lines (KG-1a, MOLM-13 and HL-60); no antigen escape
was detected in residual tumors.
Conclusions
Overall, these findings demonstrate that combinatorial targeting of CD33 or CD123
and CLL-1 with CAR T cells can control growth of heterogeneous AML tumors.
Key Words
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Article info
Publication history
Published online: December 23, 2021
Accepted:
October 11,
2021
Received:
June 23,
2021
Identification
Copyright
© 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
