Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts

• Published in: Clinical cancer research 2007-09, Vol.13 (18), p.5426-5435
• Main Authors: BRENTJENS, Renier J, SANTOS, Elmer, NIKHAMIN, Yan, YEN, Raymond, MATSUSHITA, Maiko, LA PERLE, Krista, QUINTAS-CARDAMA, Alfonso, LARSON, Steven M, SADELAIN, Michel
• Format: Article
• Language: English
• Subjects: Adoptive T cell immunotherapy; Animals; Antigens, CD19 - immunology; Antineoplastic agents; Biological and medical sciences; Cellular immunotherapy; Chimeric Antigen Receptors; Disease Models, Animal; Hematologic and hematopoietic diseases; Humans; Immunotherapy, Adoptive - methods; Leukemias and lymphomas; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred Strains; Noninvasive imaging in animal models; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Retroviridae - genetics; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Xenograft Model Antitumor Assays; Xenograft models
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0674

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.