title: Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA. brentjer@mskcc.org
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
authors.forename: Elmer
authors.initials: E
authors.lastname: Santos
authors.forename: Yan
authors.initials: Y
authors.lastname: Nikhamin
authors.forename: Raymond
authors.initials: R
authors.lastname: Yeh
authors.forename: Maiko
authors.initials: M
authors.lastname: Matsushita
authors.forename: Krista
authors.initials: K
authors.lastname: La Perle
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy*; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins