Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts

作者：Renier J. Brentjens, Elmer Santos, Yan Nikhamin, Raymond Yeh, Maiko Matsushita, Krista La Perle, Alfonso Quintás‐Cardama, Steven M. Larson, Michel Sadelain · 发表于：Clinical Cancer Research · 年份：2007 · DOI：10.1158/1078-0432.ccr-07-0674 · 被引用次数：469 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Virus-based gene therapy research

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 ta...