CD19 CAR-Targeted T Cells Induce Long-Term Remission and B Cell Aplasia in an Immunocompetent Mouse Model of B Cell Acute Lymphoblastic Leukemia Journal Article

Authors: Davila, M. L.; Kloss, C. C.; Gunset, G.; Sadelain, M.
Article Title: CD19 CAR-Targeted T Cells Induce Long-Term Remission and B Cell Aplasia in an Immunocompetent Mouse Model of B Cell Acute Lymphoblastic Leukemia
Abstract: Although many adults with B cell acute lymphoblastic leukemia (B-ALL) are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs) and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL. © 2013 Davila et al.
Keywords: signal transduction; cancer chemotherapy; cancer survival; controlled study; unclassified drug; nonhuman; antigens, cd3; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; mus; gene expression; animal experiment; cyclophosphamide; in vivo study; in vitro study; acute lymphoblastic leukemia; cell lineage; b-lymphocytes; transduction, genetic; disease model; t lymphocyte receptor; cancer regression; receptors, antigen, t-cell; antineoplastic agents, alkylating; murinae; remission induction; chimeric antigen receptor; cell therapy; adoptive transfer; precursor cell lymphoblastic leukemia-lymphoma; immunophenotyping; disease models, animal; drug dose increase; immunotherapy, adoptive; t lymphocyte activation; lymphocyte depletion; cd19 antigen; lymphocyte antigen receptor; antigens, cd19; cd28 antigen; antigens, cd28; immunocompetence; pre b lymphocyte; tumor cell destruction; mutant chimeric proteins; lymphocyte subpopulation; lymphocyte antigen; aplasia; cd3zeta antigen; b cell aplasia; cd19 chimeric antigen receptor targeted t cell therapy; conditioning chemotherapy
Journal Title: PLoS ONE
Volume: 8
Issue: 4
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2013-04-09
Start Page: e61338
Language: English
PROVIDER: scopus
PMCID: PMC3621858
PUBMED: 23585892
DOI: 10.1371/journal.pone.0061338
Notes: --- - "Export Date: 1 May 2013" - ":doi 10.1371/journal.pone.0061338" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Marco Luis Davila
    24 Davila
  2. Michel W J Sadelain
    486 Sadelain
  3. Gertrude Mary Gunset
    14 Gunset