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Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells
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Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells
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Journal Article
Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells
2024
Overview
CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/21
/ 13/31
/ 13/44
/ 13/51
/ 14/35
/ 38/5
/ 64/60
/ 82/103
/ 82/16
/ 82/58
/ 82/83
/ Adapters
/ Animals
/ Antigens
/ Humans
/ Immunotherapy, Adoptive - methods
/ Leukemia
/ Leukemia, Myeloid, Acute - immunology
/ Leukemia, Myeloid, Acute - pathology
/ Leukemia, Myeloid, Acute - therapy
/ Lysis
/ Medicine
/ Mice
/ Oncology
/ Receptors, Chimeric Antigen - immunology
/ Receptors, Chimeric Antigen - metabolism
