Long-term in vivo microscopy of CAR T cell dynamics during eradication of CNS lymphoma in mice.
Animals
Antigens, CD19
/ analysis
Cell Count
Cell Movement
Central Nervous System Neoplasms
/ diagnostic imaging
Cytotoxicity, Immunologic
Forkhead Transcription Factors
/ genetics
Humans
Immunotherapy, Adoptive
/ methods
Injections, Intravenous
Injections, Intraventricular
Intravital Microscopy
/ methods
Lymphoma
/ diagnostic imaging
Male
Mice, Mutant Strains
Neoplasms, Experimental
/ pathology
Receptors, Chimeric Antigen
/ genetics
Spatio-Temporal Analysis
T-Lymphocytes
/ immunology
Xenograft Model Antitumor Assays
2-photon microscopy
CAR T cells
PCNSL
tumor immunology
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
26 11 2019
26 11 2019
Historique:
pubmed:
13
11
2019
medline:
28
4
2020
entrez:
13
11
2019
Statut:
ppublish
Résumé
T cells expressing anti-CD19 chimeric antigen receptors (CARs) demonstrate impressive efficacy in the treatment of systemic B cell malignancies, including B cell lymphoma. However, their effect on primary central nervous system lymphoma (PCNSL) is unknown. Additionally, the detailed cellular dynamics of CAR T cells during their antitumor reaction remain unclear, including their intratumoral infiltration depth, mobility, and persistence. Studying these processes in detail requires repeated intravital imaging of precisely defined tumor regions during weeks of tumor growth and regression. Here, we have combined a model of PCNSL with in vivo intracerebral 2-photon microscopy. Thereby, we were able to visualize intracranial PCNSL growth and therapeutic effects of CAR T cells longitudinally in the same animal over several weeks. Intravenous (i.v.) injection resulted in poor tumor infiltration of anti-CD19 CAR T cells and could not sufficiently control tumor growth. After intracerebral injection, however, anti-CD19 CAR T cells invaded deeply into the solid tumor, reduced tumor growth, and induced regression of PCNSL, which was associated with long-term survival. Intracerebral anti-CD19 CAR T cells entered the circulation and infiltrated distant, nondraining lymph nodes more efficiently than mock CAR T cells. After complete regression of tumors, anti-CD19 CAR T cells remained detectable intracranially and intravascularly for up to 159 d. Collectively, these results demonstrate the great potential of anti-CD19 CAR T cells for the treatment of PCNSL.
Identifiants
pubmed: 31712432
pii: 1903854116
doi: 10.1073/pnas.1903854116
pmc: PMC6883823
doi:
Substances chimiques
Antigens, CD19
0
CD19 molecule, human
0
Forkhead Transcription Factors
0
Receptors, Chimeric Antigen
0
Whn protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
24275-24284Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: S.P.F., I.v.M.-H., S.L., X.Z., H.I.-A., J.L., W.Z., S.D., M.S., M.R., A.S., V.R.B., and L.v.B. declare that they have no competing interests. M.M. has been a member of a scientific advisory committee for Gilead. M.D. has been a member of a scientific advisory committee for Novartis. M.v.B.-B. received research funding from Miltenyi Biotech and Novartis and honoraria from Kite/Gilead. D.H.B. is cofounder of STAGE cell therapeutics GmbH (now Juno Therapeutics/Celgene) and T Cell Factory B.V. (now Kite/Gilead). D.H.B. has a consulting contract with and receives sponsored research support from Juno Therapeutics. The authors have no additional financial interests.
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