title: Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck.
abstract: OBJECTIVE
  This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN).
  
  
  METHODS
  Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m(2) on days 1, 22, and 43) and dose-escalating (10(6), 10(6), 10(6), 10(6) pfu/mL for cohort 1; 10(6), 10(7), 10(7), 10(7) for cohort 2; 10(6), 10(8), 10(8), 10(8) for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored.
  
  
  RESULTS
  Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months).
  
  
  CONCLUSIONS
  JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 10(6), 10(8), 10(8), 10(8). Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN.
authors.affiliation: Institute of Cancer Research, 237 Fulham Road, London, United Kingdom. Kevin.Harrington@icr.ac.uk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Mohan
authors.initials: M
authors.lastname: Hingorani
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Tanay
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hickey
authors.forename: Shreerang A
authors.initials: SA
authors.lastname: Bhide
authors.forename: Peter M
authors.initials: PM
authors.lastname: Clarke
authors.forename: Louise C
authors.initials: LC
authors.lastname: Renouf
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.forename: Amen
authors.initials: A
authors.lastname: Sibtain
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
authors.forename: Kate L
authors.initials: KL
authors.lastname: Newbold
authors.forename: Howard
authors.initials: H
authors.lastname: Goldsweig
authors.forename: Robert
authors.initials: R
authors.lastname: Coffin
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D006258:Head and Neck Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods*; D018139:Simplexvirus / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D000970:Antineoplastic Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002945:Cisplatin