GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab.
Animals
Cell Line
Cell Line, Tumor
Female
Glypicans
/ genetics
Humans
Immunotherapy, Adoptive
Male
Mice
Mice, Inbred C57BL
Programmed Cell Death 1 Receptor
/ immunology
Receptors, Antigen, T-Cell
/ immunology
Receptors, Chimeric Antigen
/ immunology
T-Lymphocytes
/ immunology
Xenograft Model Antitumor Assays
CAR-T cells
adverse effects
anti-PD-1 Ab
cancer biology
combination immunotherapy
human
mouse
solid tumor
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
31 03 2020
31 03 2020
Historique:
received:
17
06
2019
accepted:
12
03
2020
entrez:
2
4
2020
pubmed:
2
4
2020
medline:
24
3
2021
Statut:
epublish
Résumé
Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.
Identifiants
pubmed: 32228854
doi: 10.7554/eLife.49392
pii: 49392
pmc: PMC7108862
doi:
pii:
Substances chimiques
GPC1 protein, human
0
Glypicans
0
Programmed Cell Death 1 Receptor
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministry of Education, Culture, Sports, Science, and Technology
ID : 262221005
Organisme : Japan Agency for Medical Research and Development
ID : 14069014
Informations de copyright
© 2020, Kato et al.
Déclaration de conflit d'intérêts
DK, TY, TI, YK, KM, KT, YT, MT, HK, HA, KT, SS, TN, RN, TN, YK No competing interests declared
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