title: Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.
abstract: Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.
authors.affiliation: Department of Tumor-/Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Aliperta
authors.affiliation: Department of Tumor-/Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.|University Cancer Center (UCC), Technical University Dresden, Tumorimmunology, Dresden, Germany.|Cellex Patient Treatment GmbH, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Cartellieri
authors.affiliation: Department of Tumor-/Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Feldmann
authors.affiliation: Department of Tumor-/Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Arndt
authors.affiliation: Department of Tumor-/Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Koristka
authors.affiliation: University Cancer Center (UCC), Technical University Dresden, Tumorimmunology, Dresden, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Michalk
authors.affiliation: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von Bonin
authors.affiliation: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.|GEMoaB Monoclonals GmbH, Blasewitzer Strasse 41, Dresden, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ehninger
authors.affiliation: University Cancer Center (UCC), Technical University Dresden, Tumorimmunology, Dresden, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Bachmann
authors.affiliation: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bornhäuser
authors.affiliation: Department of Tumor-/Radioimmunology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.|University Cancer Center (UCC), Technical University Dresden, Tumorimmunology, Dresden, Germany.|DFG-Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany.
authors.forename: M P
authors.initials: MP
authors.lastname: Bachmann
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis* / Q000627:therapeutic use; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3