Immunotherapy with dendritic cells primed with an allogenic melanoma cell line in advanced metastatic melanoma

Abstract

20026 Background: Metastatic melanoma is characterized by an unfavorable prognosis. The reported median overall survival times are less than 10 months. Here we show that immunotherapy with monocyte-derived dendritic cells (MoDC) primed with an allogeneic cell line known to express a wide pattern of melanoma specific antigens can induce clinical responses in metastatic melanoma after failure of standard therapies. Methods: After isolating monocytes from peripheral blood of n=52 patients (n=27 with single metastatic organ, n=24 with more than one metastatic organ) MoDC were generated using standard protocols. The MoDC were primed on day 5 with tumor-lysate prepared from an allogeneic melanoma cell line and co-cultured with poly:IC and IFN-α. The MoDC were harvested on day 7 and administered to the patients, intradermally. Previously we showed that a high IL-12 and low IL-10 production by the MoDC was correlated to the clinical response. Culture conditions were tested for downregulation of IL-10 and simultaneous upregulation of IL-12 secretion by ELISPOT. Results: We were able to induce a clinical response in 42% (n=22) of the patients. The median survival after onset of DC-therapy was 7 months and after diagnosis of metastasis 17 months. At 12 months after diagnosis of metastasis, patients with brain metastases have the shortest median overall survival. The longest median overall survival is seen in patients with local or lymph node metastasis (29 months). Using culture conditions with sequential supplementation of a synthetic lipopeptide and a synthetic LPS, we are able to change an IL-12/IL-10 production profile < 1 to an IL12/IL-10 production file >1, which favours a TH-1 response. Conclusions: From our observations, immunotherapy with dendritic cells primed with an allogeneic cell line may prolong the overall survival of patients with metastatic melanoma. Treatment failure can be due to weak stimulation of CTL response due to a secretion of IL-10 dominating IL-12. We also demonstrated that certain danger signals can induce an upregulation of IL-12 and downregulation of IL-10 secretion in vitro and thus may improve the overall response and survival rates. No significant financial relationships to disclose.