Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial

Abstract

Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-γ ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed.

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

“…Thus far, no clinical trials have been reported that exclusively tested the combination of chemotherapy and DC vaccination, but numerous trials are ongoing in which the combination is being tested with or without additional therapies. Chemotherapy and DC vaccination were tested with the addition of a COX-2 inhibitor in melanoma in a phase III trial showing encouraging data, and with the addition of autologous T cells in lung cancer in two randomized trials showing longer overall survival compared with outcomes from chemotherapy alone (79)(80)(81).…”

Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells

“…[8][9][10]57 To improve clinical efficacy, it is probably necessary to combine vaccination with checkpoint modulators or other strategies countering immunological tolerance. 6,25,52,[66][67][68][69][70][71] As a combination strategy will increase the risk of side effects, it is encouraging that our vaccine study indicated low toxicity, even after long-term follow-up. One may further note that the longterm survivors (M22 and M109) responded well to treatment with ipilimumab.…”

Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine

“…instead of antigen peptides, antigen peptide-pulsed Dcs should have been used for priming in DtH. on this note, ellebaek et al reported that antigen-pulsed Dcs should be used as antigen in DtH test in order to present antigens to obtain the highest local immune reactivity (27). also in vitro, the reactivity of patient's cD3 + t cells against Sart1 peptide/KLH-pulsed moDCs increased after three times DC vaccination.…”