title: Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects.
abstract: The deregulation of the epidermal growth factor receptor (EGFR) has a significant role in the progression of tumors. Despite the development of a number of EGFR-targeting agents that can arrest tumor growth, their success in the clinic is limited in several tumor types, particularly in the highly malignant glioblastoma multiforme (GBM). In this study, we generated and characterized EGFR-specific nanobodies (ENb) and imageable and proapoptotic ENb immunoconjugates released from stem cells (SC) to ultimately develop a unique EGFR-targeted therapy for GBM. We show that ENbs released from SCs specifically localize to tumors, inhibit EGFR signaling resulting in reduced GBM growth and invasiveness in vitro and in vivo in both established and primary GBM cell lines. We also show that ENb primes GBM cells for proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Furthermore, SC-delivered immunoconjugates of ENb and TRAIL target a wide spectrum of GBM cell types with varying degrees of TRAIL resistance and significantly reduce GBM growth and invasion in both established and primary invasive GBM in mice. This study demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Jeroen A J M
authors.initials: JA
authors.lastname: van de Water
authors.forename: Tugba
authors.initials: T
authors.lastname: Bagci-Onder
authors.forename: Aayush S
authors.initials: AS
authors.lastname: Agarwal
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Rob C
authors.initials: RC
authors.lastname: Roovers
authors.forename: Yanni
authors.initials: Y
authors.lastname: Zhu
authors.forename: Randa
authors.initials: R
authors.lastname: Kasmieh
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhere
authors.forename: Paul M P
authors.initials: PM
authors.lastname: Van Bergen en Henegouwen
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D066246:ErbB Receptors / Q000276:immunology*; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D058953:Neural Stem Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D015398:Signal Transduction / Q000276:immunology; D061905:Single-Domain Antibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018796:Immunoconjugates; D061905:Single-Domain Antibodies; D053221:TNF-Related Apoptosis-Inducing Ligand; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors