title: A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor.
abstract: OBJECTIVE
  To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEXGM-CSF) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies.
  
  
  METHODS
  The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 10(6), 10(7), and 10(8) plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens.
  
  
  RESULTS
  The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed.
  
  
  CONCLUSIONS
  Onco VEXGM-CSF is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen.
authors.affiliation: Department of Cancer Medicine, Imperial College School of Medicine, Royal Marsden Hospital, London, UK.
authors.forename: Jennifer C C
authors.initials: JC
authors.lastname: Hu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Coffin
authors.forename: Ceri J
authors.initials: CJ
authors.lastname: Davis
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Graham
authors.forename: Natasha
authors.initials: N
authors.lastname: Groves
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Guest
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
authors.forename: Colin A
authors.initials: CA
authors.lastname: Love
authors.forename: Iain
authors.initials: I
authors.lastname: McNeish
authors.forename: Louise C
authors.initials: LC
authors.lastname: Medley
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Michael
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.forename: Claire A
authors.initials: CA
authors.lastname: Shorrock
authors.forename: Julie
authors.initials: J
authors.lastname: Simpson
authors.forename: Jan
authors.initials: J
authors.lastname: Steiner
authors.forename: Neil M
authors.initials: NM
authors.lastname: Steven
authors.forename: Dennis
authors.initials: D
authors.lastname: Wright
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood; D001706:Biopsy; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy; D002277:Carcinoma / Q000473:pathology / Q000628:therapy; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000097:blood; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses; D011994:Recombinant Proteins; D018139:Simplexvirus / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D000974:Antibodies, Antinuclear; D016207:Cytokines; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor