Fourth-generation chimeric antigen receptor T cells targeting folate receptor alpha antigen expressed on breast cancer cells for adoptive T cell therapy.
Adoptive cell therapy
Breast cancer
Chimeric antigen receptor (CAR) T cell
Folate receptor alpha (FRα)
Immunotherapy
Journal
Breast cancer research and treatment
ISSN: 1573-7217
Titre abrégé: Breast Cancer Res Treat
Pays: Netherlands
ID NLM: 8111104
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
07
09
2020
accepted:
19
11
2020
pubmed:
4
1
2021
medline:
24
6
2021
entrez:
3
1
2021
Statut:
ppublish
Résumé
Treatment of breast cancer (BC) by standard methods is effective in the early stage, but ineffective in the advanced stage of disease. To develop an adoptive T cell therapy for advanced and severe BC, we generated fourth-generation chimeric antigen receptor (CAR) T cells targeting folate receptor alpha antigen (FRα) expressed on BC cells, and preclinically evaluated their anti-BC activities. The fourth-generation FRα-CAR T cells containing extracellular FRα-specific single-chain variable fragment (scFv) and three intracellular costimulatory domains (CD28, 4-1BB, and CD27) linked to CD3ζ were generated using a lentiviral system, and then were evaluated for their anti-BC activities in two-dimensional and three-dimensional (spheroid) cultures. When our fourth-generation FRα-CAR T cells were cocultured with FRα-expressing MDA-MB-231 BC cell line at an effector to target ratio of 20:1, these CAR T cells specifically lysed 88.7 ± 10.6% of the target cells. Interestingly, the cytotoxic lysis of FRα-CAR T cells was more pronounced in target cells with higher surface FRα expression. This specific cytotoxicity of the CAR T cells was not observed when cocultured with FRα-negative MCF10A normal breast-like cell line at the same ratio (34.3 ± 4.7%). When they were cocultured with MDA-MD-231 spheroid, the FRα-CAR T cells exhibited antitumor activity marked with spheroid size reduction and breakage. This proof-of-concept study thus shows the feasibility of using these fourth-generation FRα-CAR T cells for adoptive T cell therapy in BC.
Identifiants
pubmed: 33389403
doi: 10.1007/s10549-020-06032-3
pii: 10.1007/s10549-020-06032-3
doi:
Substances chimiques
Folate Receptor 1
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25-36Subventions
Organisme : Thailand Research Fund
ID : IRN58W0001
Organisme : Thailand Research Fund
ID : IRN5801PHDW01
Organisme : Faculty of Medicine Siriraj Hospital, Mahidol University
ID : R016333030
Organisme : Faculty of Medicine Siriraj Hospital, Mahidol University
ID : R016034008
Organisme : Faculty of Medicine Siriraj Hospital, Mahidol University
ID : Chalermphrakiat grant
Organisme : Office of the Higher Education Commission
ID : CB-61-006-01
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