A novel ex vivo isolation and expansion procedure for chimeric antigen receptor engrafted human T cells.

Marc Cartellieri, Stefanie Koristka, Claudia Arndt, Anja Feldmann, Slava Stamova, Malte von Bonin, Katrin Töpfer, Thomas Krüger, Mathias Geib, Irene Michalk, Achim Temme, Martin Bornhäuser, Dirk Lindemann, Gerhard Ehninger, Michael P Bachmann

Journal: PloS one 2015;9(4):e93745

PMID: 24699869

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Abstract

Genetically engineered T lymphocytes are a promising option for cancer therapy. Prior to adoptive transfer they have to be expanded in vitro to reach therapeutically sufficient numbers. So far, no universal method exists for selective in vitro expansion of engineered T lymphocytes. In order to overcome this problem and for proof of concept we incorporated a novel unique peptide sequence of ten amino acids as epitope (E-Tag) into the binding domains of two novel chimeric antigen receptors (ECARs) directed against either prostate stem cell antigen (PSCA) for the treatment of prostate cancer (PCa) or CD33 for the treatment of acute myeloide leukemia (AML). The epitope tag then was utilized for expanding ECAR engrafted T cells by triggering the modified T cells via a monoclonal antibody directed against the E-Tag (Emab). Moreover, the E-Tag served as an efficient selection epitope for immunomagnetic isolation of modified T cells to high purity. ECAR engrafted T cells were fully functional and mediated profound anti-tumor effects in the respective models of PCa or AML both in vitro and in vivo. The method can be integrated straightforward into clinical protocols to improve therapeutic efficiency of tumor treatment with CAR modified T lymphocytes.

Address: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Dresden, Germany.; Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany.; Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany.; Department of Neurosurgery, Section Experimental Neurosurgery and Tumor Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany.; Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.; Institute of Virology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.; Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Dresden, Germany; Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.

DOI: 10.1371/journal.pone.0093745

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MeSH Terms: Adoptive Transfer, Epitopes, Humans, Lymphocyte Activation, Receptors, Antigen, T-Lymphocytes