Melanoma patients treated with dendritic cell vaccination, interleukin-2, and metronomic cyclophosphamide: Results from a phase II trial.
ABSTRACT
Background: Several clinical trials have evaluated the effect of dendritic cell (DC) vaccination in the treatment of melanoma patients but so far the clinical results have been disappointing. In this trial metronomic cyclophosphamide (Cy) and celecoxib have been added to a treatment regimen with DC vaccination and interleukin (IL-) 2 in the intend to overcome immunosuppressive mechanisms.
Methods: 28 patients with progressive metastatic melanoma were included in this phase II trial. Vaccines consisted of autologues DCs pulsed with survivin, hTERT and p53 derived peptides (HLA-A2+) or tumor lysate (HLA-A2–). Vaccine no. 1-4 was given weekly, vaccine 5-10 biweekly and monthly vaccines thereafter until disease progression. Concomitantly the patient was treated with IL-2, 2 MIU for five days following each vaccine, Cy 50 mg twice a day every second week and Celecoxib 200 mg daily. Objectives were safety and tolerability, immunological and clinical responses, time to progression (TTP) and overall survival (OS).
Results: The treatment was safe and no grade 3 or 4 adverse events were observed. 16 patients (57%) had SD according to RECIST at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). There were no differences in prognostic factors between the patients with SD and progressive disease (PD) at 1st evaluation. Vaccine induced immune responses have been observed and 5 out of 6 patients with increasing immune responses had SD; the 6th patient had prolonged OS (+ 20 months). Despite the use of metronomic Cy blood level of regulatory T cells (Treg) increased during treatment. The median TTP was 4.5 months and the median OS was 9 months. Patients with SD had a median OS at 13.7 months; patients with PD had an OS at 6.0 months (p = 0.02).
Conclusions: It seems that a vaccine induced immune response is more common among patients who achieve SD during treatment. When comparing results from a previous trial without Cy we see that the number of patients obtaining SD more than doubled (57% vs. 24%), PFS was prolonged but unfortunately OS did not improve. Notably, metronomic Cy was unable to reduce Treg level.