GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): A phase I trial in melanoma

Background:Ineffective tumour antigen processing is recognisedas an important cause of failure of immunotherapy in melanoma. GM-CSF mayaugment the cytotoxic lymphocyte response by activating antigen-presentingcells. This study evaluates a schedule combining GM-CSF with biochemotherapy.Patients and methods:Nineteen patients with advanced malignantmelanoma received cisplatin (25 mg/m² days 1–3), dacarbazine(220 mg/m² days 1–3), interleukin-2 (9 MIU/m²/24h)and interferon-2b (5 MIU/m²) both days 6–10 and days17–21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF wasgiven in escalating doses to three cohorts: 1) 450 µg/m² days4–5 and 15–16; 2) as 1) plus 225 µg/m² days6–10 and 17–21; 3) 450 µg/m² days 4–10 and15–21. Each cycle was 28 days.Results:Constitutional side effects were the majornon-haematological toxicity and lymphopaenia the main haematological toxicity.Six patients responded (32%, 95% confidence interval:13%–57%), two patients had complete remission. There wasan apparent trend for increasing responses with increasing GM-CSF dose; zeroof six responses in cohort 1, two of seven in cohort 2 and three of six incohort 3 (P = 0.016). Median overall survival was 6.2 months.Increasing GM-CSF doses significantly increased serum concentrations ofneopterin and TNF-.Conclusions:The combination of GM-CSF with biochemotherapy isfeasible and there appears to be a dose-response relationship with GM-CSF interms of host immunological response, and possibly clinical efficacy.