Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts Journal Article

Authors: Brentjens, R. J.; Santos, E.; Nikhamin, Y.; Yeh, R.; Matsushita, M.; La Perle, K.; Quintas-Cardama, A.; Larson, S. M.; Sadelain, M.
Article Title: Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts
Abstract: Purpose: Human T cells targeted to the B cell-specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy. Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors. Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement. Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy. © 2007 American Association for Cancer Research.
Keywords: controlled study; human cell; nonhuman; antigen expression; t lymphocyte; t-lymphocytes; mouse; animals; mice; animal tissue; gene targeting; animal experiment; animal model; antineoplastic activity; xenograft model antitumor assays; acute lymphoblastic leukemia; mice, inbred strains; survival time; recombinant fusion proteins; xenograft; precursor cell lymphoblastic leukemia-lymphoma; disease models, animal; bioluminescence; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; lymphocyte antigen receptor; antigens, cd19; lymphocyte function; retroviridae; receptors, immunologic; lymphocyte homing
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 18
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-09-15
Start Page: 5426
End Page: 5435
Language: English
DOI: 10.1158/1078-0432.ccr-07-0674
PUBMED: 17855649
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 47" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Renier J Brentjens
    269 Brentjens
  2. Elmer B Santos
    25 Santos
  3. Michel W J Sadelain
    517 Sadelain
  4. Steven M Larson
    908 Larson
  5. Raymond Yeh
    18 Yeh