Off-the-shelf dual CAR-iNKT cell immunotherapy eradicates medullary and leptomeningeal high-risk KMT2A-rearranged leukemia
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
Abstract
Current therapies, including autologous CAR-T immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL), a disease characterized by frequent central nervous system involvement, poor treatment response, early relapse and lineage switching. More effective treatment strategies, including the availability of 'off-the-shelf' immunotherapies is particularly relevant in infants. PROM1/CD133 is a direct target of KMT2A-fusion oncoproteins and is expressed on leukemic cells. Allogeneic iNKT cells, 'innately' more powerful effectors than T cells can be deployed 'off-the-shelf' without risk of acute graft-versus-host disease. Here, we equip iNKT with CD19- and/or CD133-targeting CARs and investigate their anti-leukaemia activity against KMT2Ar-ALL in relevant in vitro and in vivo models. Compared to mono-specific counterparts and dual, bi-specific CAR-T, bi-specific CD19-CD133 CAR-iNKT have a more potent anti-leukemia activity, effectively targeting both CAR antigen-high and -low leukemia. Bi-specific CAR-iNKT eradicate medullary and, notably, leptomeningeal leukemia and induce sustained remissions without discernible hematologic toxicity. Mechanistically, the more potent anti-leukemia effect of CAR-iNKT over CAR-T cells is mediated by a pronounced CAR- and CAR antigen-dependent upregulation of the innate activating receptor NKG2D on CAR-iNKT and its engagement by its corresponding ligands on KMT2Ar-ALL cells. This ensures effective leukemia targeting even with downregulation of CD133 or CD19. Thus, by engaging with two different types of leukemia-associated antigens i.e., CAR antigens and NKG2D ligands, CAR-iNKT provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.
Date Issued
2026-01-08
Date Acceptance
2025-07-21
Citation
Blood, 2026, 147 (2), pp.180-196
ISSN
0006-4971
Publisher
American Society of Hematology (ASH Publications)
Start Page
180
End Page
196
Journal / Book Title
Blood
Volume
147
Issue
2
Copyright Statement
Copyright © 2025 American Society of Hematology Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40898981
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-09-03