title: Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.
abstract: The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.
authors: University Cancer Center (UCC), Carl Gustav Carus University Hospital TU-Dresden, Tumorimmunology, Dresden, Germany.|Cellex Patient Treatment GmbH, Dresden, Germany.
authors: M
authors: M
authors: Cartellieri
authors: University Cancer Center (UCC), Carl Gustav Carus University Hospital TU-Dresden, Tumorimmunology, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors: A
authors: A
authors: Feldmann
authors: University Cancer Center (UCC), Carl Gustav Carus University Hospital TU-Dresden, Tumorimmunology, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors: S
authors: S
authors: Koristka
authors: University Cancer Center (UCC), Carl Gustav Carus University Hospital TU-Dresden, Tumorimmunology, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors: C
authors: C
authors: Arndt
authors: University Cancer Center (UCC), Carl Gustav Carus University Hospital TU-Dresden, Tumorimmunology, Dresden, Germany.|GEMoaB Monoclonals GmbH, Dresden, Germany.
authors: S
authors: S
authors: Loff
authors: GEMoaB Monoclonals GmbH, Dresden, Germany.
authors: A
authors: A
authors: Ehninger
authors: University Hospital Carl Gustav Carus, Medical Clinic and Policlinic I, Dresden, Germany.
authors: M
authors: M
authors: von Bonin
authors: University Hospital Carl Gustav Carus, Medical Clinic and Policlinic I, Dresden, Germany.
authors: E P
authors: EP
authors: Bejestani
authors: University Hospital Carl Gustav Carus, Medical Clinic and Policlinic I, Dresden, Germany.
authors: G
authors: G
authors: Ehninger
authors: University Cancer Center (UCC), Carl Gustav Carus University Hospital TU-Dresden, Tumorimmunology, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors: M P
authors: MP
authors: Bachmann
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D053650:Interleukin-3 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic; D047368:Tumor Burden
chemical_list: D000951:Antigens, Neoplasm; C000605956:CD19-specific chimeric antigen receptor; C571163:CD33 protein, human; D016207:Cytokines; D053650:Interleukin-3 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D063268:Sialic Acid Binding Ig-like Lectin 3