Modeling anti-CD19 CAR T cell therapy in humanized mice with human immunity and autologous leukemia Journal Article

   

Authors:	Jin, C. H.; Xia, J.; Rafiq, S.; Huang, X.; Hu, Z.; Zhou, X.; Brentjens, R. J.; Yang, Y. G.
Article Title:	Modeling anti-CD19 CAR T cell therapy in humanized mice with human immunity and autologous leukemia
Abstract:	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. © 2018 The Authors
Keywords:	signal transduction; controlled study; leukemia; human cell; nonhuman; flow cytometry; cd3 antigen; cd8 antigen; transcription factor foxp3; cell proliferation; mouse; phenotype; cell survival; cd34 antigen; tumor volume; interleukin 10; interleukin 5; interleukin 8; animal experiment; animal model; cyclophosphamide; antineoplastic activity; transplantation; regulatory t lymphocyte; cryopreservation; fusion gene; cell therapy; cytokine production; immunity; lymphatic leukemia; cd4 antigen; gamma interferon inducible protein 10; cd34 selection; immunocompetent cell; cd19 antigen; cd28 antigen; monocyte chemotactic protein 1; cd33 antigen; interleukin 2 receptor alpha; tumor necrosis factor; b cell leukemia; immunological memory; immune reconstitution; macrophage inflammatory protein 1alpha; human; priority journal; article; bone marrow derived macrophage; receptor type tyrosine protein phosphatase c; chimeric antigen receptor immunotherapy
Journal Title:	EBioMedicine
Volume:	39
ISSN:	2352-3964
Publisher:	Elsevier Inc.
Date Published:	2019-01-01
Start Page:	173
End Page:	181
Language:	English
DOI:	10.1016/j.ebiom.2018.12.013
PUBMED:	30579863
PROVIDER:	scopus
PMCID:	PMC6354733
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85058643989&doi=10.1016%2fj.ebiom.2018.12.013&partnerID=40&md5=874f31508a20f85d6ab78b081112fa84
Notes:	Export Date: 1 February 2019 -- Source: Scopus