title: Locally-delivered T-cell-derived cellular vehicles efficiently track and deliver adenovirus delta24-RGD to infiltrating glioma.
abstract: Oncolytic adenoviral vectors are a promising alternative for the treatment of glioblastoma. Recent publications have demonstrated the advantages of shielding viral particles within cellular vehicles (CVs), which can be targeted towards the tumor microenvironment. Here, we studied T-cells, often having a natural capacity to target tumors, for their feasibility as a CV to deliver the oncolytic adenovirus, Delta24-RGD, to glioblastoma. The Jurkat T-cell line was assessed in co-culture with the glioblastoma stem cell (GSC) line, MGG8, for the optimal transfer conditions of Delta24-RGD in vitro. The effect of intraparenchymal and tail vein injections on intratumoral virus distribution and overall survival was addressed in an orthotopic glioma stem cell (GSC)-based xenograft model. Jurkat T-cells were demonstrated to facilitate the amplification and transfer of Delta24-RGD onto GSCs. Delta24-RGD dosing and incubation time were found to influence the migratory ability of T-cells towards GSCs. Injection of Delta24-RGD-loaded T-cells into the brains of GSC-bearing mice led to migration towards the tumor and dispersion of the virus within the tumor core and infiltrative zones. This occurred after injection into the ipsilateral hemisphere, as well as into the non-tumor-bearing hemisphere. We found that T-cell-mediated delivery of Delta24-RGD led to the inhibition of tumor growth compared to non-treated controls, resulting in prolonged survival (p = 0.007). Systemic administration of virus-loaded T-cells resulted in intratumoral viral delivery, albeit at low levels. Based on these findings, we conclude that T-cell-based CVs are a feasible approach to local Delta24-RGD delivery in glioblastoma, although efficient systemic targeting requires further improvement.
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. r.balvers@erasmusmc.nl.
authors.forename: Rutger K
authors.initials: RK
authors.lastname: Balvers
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. z.belcaid@erasmusmc.nl.
authors.forename: Zineb
authors.initials: Z
authors.lastname: Belcaid
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Einthovenweg 20, 2333 ZC, The Netherlands. sanne.vandenhengel@wetsus.nl.
authors.forename: Sanne K
authors.initials: SK
authors.lastname: van den Hengel
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. j.kloezeman@erasmusmc.nl.
authors.forename: Jenneke
authors.initials: J
authors.lastname: Kloezeman
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. j.devrij@erasmusmc.nl.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Vrij
authors.affiliation: Molecular Neurosurgery Laboratory, Brain Tumor Research Center, Massachusetts General Hospital, Boston, MA 02114, USA. HWakimoto@partners.org.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Einthovenweg 20, 2333 ZC, The Netherlands. r.c.hoeben@lumc.nl.
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.affiliation: Laboratory of Experimental Tumor Immunology, Department Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GE, The Netherlands. j.debets@erasmusmc.nl.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. s.leenstra@erasmusmc.nl.
authors.forename: Sieger
authors.initials: S
authors.lastname: Leenstra
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. c.dirven@erasmusmc.nl.
authors.forename: Clemens
authors.initials: C
authors.lastname: Dirven
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Dr. Molewaterplein 50, Ee2236, 3015GE, Rotterdam, The Netherlands. m.lamfers@erasmusmc.nl.
authors.forename: Martine L M
authors.initials: ML
authors.lastname: Lamfers
mesh_terms: D000256:Adenoviridae / Q000254:growth & development / Q000502:physiology*; D000818:Animals; D001691:Biological Therapy / Q000379:methods*; D002460:Cell Line; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005910:Glioma / Q000628:therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D050504:Oncolytic Viruses / Q000254:growth & development / Q000502:physiology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000821:virology*; D016896:Treatment Outcome