title: Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors.
abstract: OBJECTIVE
  Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide.
  
  
  METHODS
  In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m(2) through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose.
  
  
  RESULTS
  The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m(2) combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus.
  
  
  CONCLUSIONS
  Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.
authors.affiliation: Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Roulstone
authors.affiliation: Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Khurum
authors.initials: K
authors.lastname: Khan
authors.affiliation: Postgraduate Medical School, University of Surrey, Guildford, Surrey, United Kingdom.
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.affiliation: King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rudman
authors.affiliation: Oncolytics Biotech, Inc., Calgary, Alberta, Canada.
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.affiliation: Oncolytics Biotech, Inc., Calgary, Alberta, Canada.
authors.forename: George M
authors.initials: GM
authors.lastname: Gill
authors.affiliation: Leeds Institute of Cancer and Pathology, Leeds, United Kingdom.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Melcher
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
authors.affiliation: Chester Beatty Laboratories, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.affiliation: Royal Marsden Hospital, Down's Road, Sutton, Surrey, United Kingdom.
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.affiliation: King's College London, Guy's Hospital, London, United Kingdom. james.spicer@kcl.ac.uk.
authors.forename: James
authors.initials: J
authors.lastname: Spicer
mesh_terms: D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000187:drug effects / Q000276:immunology; D000914:Antibodies, Viral / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology*; D012087:Reoviridae / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide