PMID- 30579863
OWN - NLM
STAT- MEDLINE
DCOM- 20190610
LR  - 20200225
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 39
DP  - 2019 Jan
TI  - Modeling anti-CD19 CAR T cell therapy in humanized mice with human immunity and 
      autologous leukemia.
PG  - 173-181
LID - S2352-3964(18)30584-X [pii]
LID - 10.1016/j.ebiom.2018.12.013 [doi]
AB  - BACKGROUND: Adoptive immunotherapy using T cells expressing chimeric antigen 
      receptors (CARs) targeting CD19 has produced remarkable clinical outcomes. 
      However, much of the mechanisms of action, such as the development of memory 
      responses and sources of immune cytokines, remain elusive largely due to the 
      challenge of characterizing human CAR T cell function in vivo. The lack of a 
      suitable in vivo model also hinders the development of new CAR T cell therapies. 
      METHODS: We established a humanized mouse (hu-mouse) model with a functional 
      human immune system and genetically-matched (autologous) primary acute 
      B-lymphoblastic leukemia (B-ALL) that permits modeling of CD19-targeted CAR T 
      cell therapy in immunocompetent hosts without allogeneic or xenogeneic immune 
      responses. FINDINGS: Anti-CD19 CAR T cells were detected in blood of leukemic 
      hu-mice with kinetics and levels similar to those seen in patients receiving CAR 
      T cell therapy. The levels of CAR T cells were correlated inversely with the 
      burden of leukemia cells and positively with the survival times in anti-CD19 CAR 
      T cell-treated leukemic hu-mice. Infusion of anti-CD19 CAR T cells also resulted 
      in rapid production of T cell- and monocyte/macrophage-derived cytokines and an 
      increase in frequency of regulatory T cells as reported in clinical studies. 
      INTERPRETATION: These results provide a proof-of-principle that this novel 
      preclinical model has the potential to be used to model human CAR T cell therapy 
      and facilitate the design of new CARs with improved antitumor activity.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Jin, Chun-Hui
AU  - Jin CH
AD  - Institute of Translational Medicine, The First Hospital, Jilin University, 
      Changchun, China; International Center of Future Science, Jilin University, 
      Changchun, China; Columbia Center for Translational Immunology, Department of 
      Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 
      United States.
FAU - Xia, Jinxing
AU  - Xia J
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University College of Physicians and Surgeons, New York, NY, United States.
FAU - Rafiq, Sarwish
AU  - Rafiq S
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      United States.
FAU - Huang, Xin
AU  - Huang X
AD  - Departments of Pediatrics and Pathology, New York Medical College, Valhalla, NY, 
      United States.
FAU - Hu, Zheng
AU  - Hu Z
AD  - Institute of Translational Medicine, The First Hospital, Jilin University, 
      Changchun, China; International Center of Future Science, Jilin University, 
      Changchun, China.
FAU - Zhou, Xianzheng
AU  - Zhou X
AD  - Departments of Pediatrics and Pathology, New York Medical College, Valhalla, NY, 
      United States.
FAU - Brentjens, Renier J
AU  - Brentjens RJ
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 
      United States.
FAU - Yang, Yong-Guang
AU  - Yang YG
AD  - Institute of Translational Medicine, The First Hospital, Jilin University, 
      Changchun, China; International Center of Future Science, Jilin University, 
      Changchun, China; Columbia Center for Translational Immunology, Department of 
      Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 
      United States. Electronic address: yy2324@columbia.edu.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20181220
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Antigens, CD19)
RN  - 0 (CD19 molecule, human)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - Animals
MH  - Antigens, CD19/*immunology
MH  - Cell- and Tissue-Based Therapy
MH  - Humans
MH  - Immunotherapy, Adoptive
MH  - Leukemia, B-Cell/immunology/*therapy
MH  - Mice
MH  - Receptors, Antigen, T-Cell/*metabolism
MH  - T-Lymphocytes/immunology/*transplantation
MH  - Treatment Outcome
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC6354733
EDAT- 2018/12/24 06:00
MHDA- 2019/06/14 06:00
PMCR- 2018/12/20
CRDT- 2018/12/24 06:00
PHST- 2018/10/30 00:00 [received]
PHST- 2018/11/28 00:00 [revised]
PHST- 2018/12/07 00:00 [accepted]
PHST- 2018/12/24 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2018/12/24 06:00 [entrez]
PHST- 2018/12/20 00:00 [pmc-release]
AID - S2352-3964(18)30584-X [pii]
AID - 10.1016/j.ebiom.2018.12.013 [doi]
PST - ppublish
SO  - EBioMedicine. 2019 Jan;39:173-181. doi: 10.1016/j.ebiom.2018.12.013. Epub 2018 
      Dec 20.