1. Long-term in vivo microscopy of CAR T cell dynamics during eradication of CNS lymphoma in mice.
- Author
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Mulazzani M, Fräßle SP, von Mücke-Heim I, Langer S, Zhou X, Ishikawa-Ankerhold H, Leube J, Zhang W, Dötsch S, Svec M, Rudelius M, Dreyling M, von Bergwelt-Baildon M, Straube A, Buchholz VR, Busch DH, and von Baumgarten L
- Subjects
- Animals, Antigens, CD19 analysis, Antigens, CD19 immunology, Antigens, CD19 metabolism, Cell Count, Cell Movement, Central Nervous System Neoplasms diagnostic imaging, Central Nervous System Neoplasms pathology, Cytotoxicity, Immunologic, Forkhead Transcription Factors genetics, Humans, Injections, Intravenous, Injections, Intraventricular, Lymphoma diagnostic imaging, Lymphoma pathology, Male, Mice, Mutant Strains, Neoplasms, Experimental pathology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology, Spatio-Temporal Analysis, T-Lymphocytes immunology, Xenograft Model Antitumor Assays, Central Nervous System Neoplasms therapy, Immunotherapy, Adoptive methods, Intravital Microscopy methods, Lymphoma therapy, T-Lymphocytes transplantation
- Abstract
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., Competing Interests: 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., (Copyright © 2019 the Author(s). Published by PNAS.)
- Published
- 2019
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