title: Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity.
abstract: Reovirus is a naturally occurring oncolytic virus currently in early clinical trials. However, the rapid induction of neutralizing antibodies represents a major obstacle to successful systemic delivery. This study addresses, for the first time, the ability of cellular carriers in the form of T cells and dendritic cells (DC) to protect reovirus from systemic neutralization. In addition, the ability of these cellular carriers to manipulate the subsequent balance of anti-viral versus anti-tumour immune response is explored. Reovirus, either neat or loaded onto DC or T cells, was delivered intravenously into reovirus-naive or reovirus-immune C57Bl/6 mice bearing lymph node B16tk melanoma metastases. Three and 10 days after treatment, reovirus delivery, carrier cell trafficking, metastatic clearance and priming of anti-tumour/anti-viral immunity were assessed. In naive mice, reovirus delivered either neat or through cell carriage was detectable in the tumour-draining lymph nodes 3 days after treatment, though complete clearance of metastases was only obtained when the virus was delivered on T cells or mature DC (mDC); neat reovirus or loaded immature DC (iDC) gave only partial early tumour clearance. Furthermore, only T cells carrying reovirus generated anti-tumour immune responses and long-term tumour clearance; reovirus-loaded DC, in contrast, generated only an anti-viral immune response. In reovirus-immune mice, however, the results were different. Neat reovirus was completely ineffective as a therapy, whereas mDC--though not iDC--as well as T cells, effectively delivered reovirus to melanoma in vivo for therapy and anti-tumour immune priming. Moreover, mDC were more effective than T cells over a range of viral loads. These data show that systemically administered neat reovirus is not optimal for therapy, and that DC may be an appropriate vehicle for carriage of significant levels of reovirus to tumours. The pre-existing immune status against the virus is critical in determining the balance between anti-viral and anti-tumour immunity elicited when reovirus is delivered by cell carriage, and the viral dose and mode of delivery, as well as the immune status of patients, may profoundly affect the success of any clinical anti-tumour viral therapy. These findings are therefore of direct translational relevance for the future design of clinical trials.
authors.affiliation: Cancer Research UK, Leeds Institute of Molecular Medicine, St James' University Hospital, Leeds, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Ilett
authors.forename: R J
authors.initials: RJ
authors.lastname: Prestwich
authors.forename: T
authors.initials: T
authors.lastname: Kottke
authors.forename: F
authors.initials: F
authors.lastname: Errington
authors.forename: J M
authors.initials: JM
authors.lastname: Thompson
authors.forename: K J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: H S
authors.initials: HS
authors.lastname: Pandha
authors.forename: M
authors.initials: M
authors.lastname: Coffey
authors.forename: P J
authors.initials: PJ
authors.lastname: Selby
authors.forename: R G
authors.initials: RG
authors.lastname: Vile
authors.forename: A A
authors.initials: AA
authors.lastname: Melcher
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D016923:Cell Death; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000637:transplantation*; D008198:Lymph Nodes / Q000821:virology; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology*; D012087:Reoviridae / Q000276:immunology / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000637:transplantation*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D019562:Viral Load