A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR

Hiroki Torikai, Andreas Reik, Pei Qi Liu, Yuanyue Zhou, Ling Zhang, Sourindra Maiti, Helen Huls, Jeffrey C. Miller, Partow Kebriaei, Brian Rabinovitch, Dean A. Lee, Richard E. Champlin, Chiara Bonini, Luigi Naldini, Edward J. Rebar, Philip D. Gregory, Michael C. Holmes, Laurence J N Cooper

Research output: Contribution to journalArticlepeer-review

Abstract

Clinical-grade T cells are genetically modified ex vivo to express a chimeric antigen receptor (CAR) to redirect specificity to a tumor associated antigen (TAA) thereby conferring antitumor activity in vivo. T cells expressing a CD19-specific CAR recognize B-cell malignancies in multiple recipients independent of major histocompatibility complex (MHC) because the specificity domains are cloned from the variable chains of a CD19 monoclonal antibody. We now report a major step toward eliminating the need to generate patient-specific T cells by generating universal allogeneic TAA-specific T cells from one donor that might be administered to multiple recipients. This was achieved by genetically editing CD19-specific CAR+ T cells to eliminate expression of the endogenous αβ T-cell receptor (TCR) to prevent a graft-versus-host response without compromising CAR-dependent effector functions. Genetically modified T cells were generated using the Sleeping Beauty system to stably introduce the CD19-specific CAR with subsequent permanent deletion of α or β TCR chains with designer zinc finger nucleases. We show that these engineered T cells display the expected property of having redirected specificity for CD19 without responding to TCR stimulation. CAR+TCRneg T cells of this type may potentially have efficacy as an off-the-shelf therapy for investigational treatment of B-lineage malignancies.

Original languageEnglish
Pages (from-to)5697-5705
Number of pages9
JournalBlood
Volume119
Issue number24
DOIs
Publication statusPublished - Jun 14 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Fingerprint Dive into the research topics of 'A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR'. Together they form a unique fingerprint.

Cite this