Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts

Renier J. Brentjens, Elmer Santos, Yan Nikhamin, Raymond Yeh, Maiko Matsushita, Krista La Perle, Alfonso Quintás-Cardama, Steven M. Larson, Michel Sadelain

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275 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5426-5435
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
Publication statusPublished - 2007 Sep 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Brentjens, R. J., Santos, E., Nikhamin, Y., Yeh, R., Matsushita, M., La Perle, K., Quintás-Cardama, A., Larson, S. M., & Sadelain, M. (2007). Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clinical Cancer Research, 13(18), 5426-5435. https://doi.org/10.1158/1078-0432.CCR-07-0674