Dual antigen-targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
08 12 2022
08 12 2022
Historique:
accepted:
11
07
2022
received:
19
12
2021
pubmed:
3
8
2022
medline:
15
12
2022
entrez:
2
8
2022
Statut:
ppublish
Résumé
Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity. In addition, we introduced a membrane-bound IL-15/IL-15R fusion protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19- lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.
Identifiants
pubmed: 35917442
pii: S0006-4971(22)00973-9
doi: 10.1182/blood.2021015184
pmc: PMC9918847
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2451-2462Subventions
Organisme : NCI NIH HHS
ID : P01 CA065493
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA203348
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197292
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA111412
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL155150
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by The American Society of Hematology.
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