title: Effective Eradication of Glioblastoma Stem Cells by Local Application of an AC133/CD133-Specific T-cell-Engaging Antibody and CD8 T Cells.
abstract: Cancer stem cells (CSC) drive tumorigenesis and contribute to genotoxic therapy resistance, diffuse infiltrative invasion, and immunosuppression, which are key factors for the incurability of glioblastoma multiforme (GBM). The AC133 epitope of CD133 is an important CSC marker for GBM and other tumor entities. Here, we report the development and preclinical evaluation of a recombinant AC133×CD3 bispecific antibody (bsAb) that redirects human polyclonal T cells to AC133(+) GBM stem cells (GBM-SC), inducing their strong targeted lysis. This novel bsAb prevented the outgrowth of AC133-positive subcutaneous GBM xenografts. Moreover, upon intracerebral infusion along with the local application of human CD8(+) T cells, it exhibited potent activity in prophylactic and treatment models of orthotopic GBM-SC-derived invasive brain tumors. In contrast, normal hematopoietic stem cells, some of which are AC133-positive, were virtually unaffected at bsAb concentrations effective against GBM-SCs and retained their colony-forming abilities. In conclusion, our data demonstrate the high activity of this new bsAb against patient-derived AC133-positive GBM-SCs in models of local therapy of highly invasive GBM.
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Gaedicke
authors.affiliation: Department of Neurosurgery, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Marcia
authors.initials: M
authors.lastname: Machein
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mittler
authors.affiliation: Faculty of Biology, University of Freiburg, Freiburg, Germany. Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Braun
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hettich
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Firat
authors.affiliation: Oncotest GmbH, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klingner
authors.affiliation: Oncotest GmbH, Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wider
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Wäsch
authors.affiliation: Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Department of Urology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Elsässer-Beile
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany. gabriele.niedermann@uniklinik-freiburg.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
mesh_terms: D000071916:AC133 Antigen; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology* / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D063646:Carcinogenesis / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D000939:Epitopes / Q000276:immunology; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006023:Glycoproteins / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000071916:AC133 Antigen; D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000939:Epitopes; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides