CARs are constructed from the genes encoding a single-chain variable fragment (scFv) of a TAA-specific monoclonal antibody (mAb), extracellular hinge or scaffold with transmembrane domain, and portions of CD3ζ and CD28 or CD137 (4-1BB) endodomains. T cells can be rendered specific for tumor-associated antigens (TAAs) independent of their endogenous T-cell receptor (TCR) via gene transfer of chimeric antigen receptors (CARs). This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. He receives honoraria from Miltenyi Biotec. He is on the Scientific Advisory Board of Cellectis. (formerly American Stem cells, Inc.), GE Healthcare, Ferring Pharmaceuticals, Fate Therapeutics, Janssen Pharmaceuticals, and Bristol-Myers Squibb. He has patents with Sangamo BioSciences with artificial nucleases. Cooper founded and owns InCellerate, Inc. Thomas Scott MDACC Moon Shot National Foundation for Cancer Research Pediatric Cancer Research Foundation Production Assistance for Cellular Therapies (PACT) TeamConnor Thomas Scott William Lawrence and Blanche Hughes Children's Foundation.Ĭompeting interests: Dr. Mangurian, Jr., Fund for Leukemia Immunotherapy Fund for Leukemia Immunotherapy Institute of Personalized Cancer Therapy Leukemia and Lymphoma Society SCOR Lymphoma Research Foundation Miller Foundation Mr. Bibler Gillson Longenbaugh Foundation Harry T. Ward Foundation Burroughs Wellcome Fund Cancer Prevention and Research Institute of Texas CLL Global Research Foundation Department of Defense Estate of Noelan L. The work is made available under the Creative Commons CC0 public domain dedicationĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This work was supported by funding from: Cancer Center Core Grant (CA16672) RO1 (CA124782, CA120956, CA141303 CA141303) R33 (CA116127) P01 (CA148600) S10RR026916 SPORE (CA83639) Albert J. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Received: FebruAccepted: ApPublished: June 1, 2015 PLoS ONE 10(6):Īcademic Editor: Derya Unutmaz, Jackson Laboratory, UNITED STATES (2015) Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations. Clinical trials will investigate the ability of ROR1-specific CAR + T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire.Ĭitation: Deniger DC, Yu J, Huls MH, Figliola MJ, Mi T, Maiti SN, et al. Moreover, such cells could eliminate ROR1 + tumor xenografts, especially T cells expressing ROR1RCD137. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1 + tumors. ![]() Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR + T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Two Sleeping Beauty transposons were constructed with 2 nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. However, this is often accompanied by a loss of normal CD19 + B cells and humoral immunity. T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies.
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