Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy.
Cytotherapy
; 24(3): 282-290, 2022 03.
Article
in En
| MEDLINE
| ID: mdl-34955406
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
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia, Lymphocytic, Chronic, B-Cell
/
Leukemia, Myeloid, Acute
Limits:
Animals
Language:
En
Journal:
Cytotherapy
Journal subject:
TERAPEUTICA
Year:
2022
Type:
Article
Affiliation country:
United States