CD123 CAR T cells for the treatment of myelodysplastic syndrome.
Exp Hematol
; 74: 52-63.e3, 2019 06.
Article
en En
| MEDLINE
| ID: mdl-31136781
ABSTRACT
Myelodysplastic syndrome (MDS) is a group of heterogeneous disorders caused by ineffective hematopoiesis and characterized by bone marrow dysplasia and cytopenia. Current treatment options for MDS are limited to supportive care, hypomethylating agents, and stem cell transplant. Most patients eventually succumb to the disease or progress to leukemia. Previously, we found that CD123 can be used to delineate MDS stem cells in patients at high risk for MDS and that the CD123-positive population is biologically distinct from normal hematopoietic stem cells. Furthermore, selective targeting of MDS stem cells can dramatically reduce tumor burden in preclinical models. On the basis of these findings, we propose CD123 as a candidate target for chimeric antigen receptor (CAR) T-cell therapy in high-risk MDS patients. To test this concept, we employed a CAR lentiviral vector containing a CD123-specific single-chain variable fragment in combination with the CD28 costimulatory domain, CD3ζ signaling domain, and truncated estimated glomerular filtration rate. Utilizing this system, we illustrate that CD123 CAR can be expressed on both healthy donor and MDS patient-derived T lymphocytes with high efficiency, leading to the successful elimination of MDS stem cells both in vitro and in patient-derived xenografts. These results provide the concept for the use of CD123-targeted CAR T cells as a therapeutic option for patients with MDS.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Síndromes Mielodisplásicos
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Inmunoterapia Adoptiva
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Subunidad alfa del Receptor de Interleucina-3
/
Receptores Quiméricos de Antígenos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Exp Hematol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Colombia