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.
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.
Harrington
Kevin J
KJ
Institute of Cancer Research, 237 Fulham Road, London, United Kingdom. Kevin.Harrington@icr.ac.uk
Hingorani
Mohan
M
Tanay
Mary Anne
MA
Hickey
Jennifer
J
Bhide
Shreerang A
SA
Clarke
Peter M
PM
Renouf
Louise C
LC
Thway
Khin
K
Sibtain
Amen
A
McNeish
Iain A
IA
Newbold
Kate L
KL
Goldsweig
Howard
H
Coffin
Robert
R
Nutting
Christopher M
CM
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
D000914:Antibodies, Viral; D000956:Antigens, Viral; D000970:Antineoplastic Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002945:Cisplatin