Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients.
Adenine
/ analogs & derivatives
Antigens, CD19
/ immunology
CD4-Positive T-Lymphocytes
/ cytology
CD8-Positive T-Lymphocytes
/ cytology
Case-Control Studies
Cell Culture Techniques
Culture Media
Cytokines
/ biosynthesis
HEK293 Cells
Humans
Immunotherapy, Adoptive
/ methods
K562 Cells
Leukemia, Lymphocytic, Chronic, B-Cell
/ immunology
Piperidines
/ pharmacology
Receptors, Antigen, T-Cell
/ biosynthesis
Receptors, Chimeric Antigen
/ immunology
T-Lymphocyte Subsets
/ cytology
Burton's tyrosine kinase (BTK)
chimeric antigen receptor (CAR)
chronic lymphocytic leukemia (CLL)
ibrutinib
immunotherapy
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 01 2021
15 01 2021
Historique:
received:
04
03
2020
revised:
05
06
2020
accepted:
03
07
2020
pubmed:
20
7
2020
medline:
9
6
2021
entrez:
20
7
2020
Statut:
ppublish
Résumé
Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.
Substances chimiques
Antigens, CD19
0
CD19 molecule, human
0
CD19-specific chimeric antigen receptor
0
Culture Media
0
Cytokines
0
Piperidines
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
ibrutinib
1X70OSD4VX
Adenine
JAC85A2161
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
419-428Informations de copyright
© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.
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