title: The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.
abstract: The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.
authors.affiliation: Dept of Neurosurgery, Brain Tumor Center, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Kleijn
authors.affiliation: Dept of Neurosurgery, Brain Tumor Center, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Jenneke
authors.initials: J
authors.lastname: Kloezeman
authors.affiliation: Laboratory of Experimental Tumor Immunology, Dept of Medical Oncology, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Elike
authors.initials: E
authors.lastname: Treffers-Westerlaken
authors.affiliation: Brain Tumor Research Center, Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fulci
authors.affiliation: Dept of Neurosurgery, Brain Tumor Center, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Sieger
authors.initials: S
authors.lastname: Leenstra
authors.affiliation: Dept of Neurosurgery, Brain Tumor Center, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Dirven
authors.affiliation: Laboratory of Experimental Tumor Immunology, Dept of Medical Oncology, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.affiliation: Dept of Neurosurgery, Brain Tumor Center, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Lamfers
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy / Q000821:virology; D049109:Cell Proliferation; D005260:Female; D005910:Glioma / Q000276:immunology* / Q000401:mortality / Q000628:therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000627:therapeutic use*; D050130:Oncolytic Virotherapy; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid