A cohort pilot study on therapeutic vaccination of advanced melanoma patients with dendritic cells loaded with multiple peptides or electroporated with mRNA

Abstract

18011 Background: Therapeutic vaccination of melanoma patients with tumor specific antigenic peptides has been associated with increased frequency of anti-vaccine CTL precursor frequencies in peripheral blood and objective tumor regression in a low percentage of patients. Methods: We investigated the safety and activity of two autologous dendritic cell-based vaccines in 2 sequential cohorts of advanced melanoma patients. Patients first underwent a leucapheresis. Following enrichment in a semi-closed culture system using Cell Factories (Nunc), adherent cells were cultured in RPMI 1640 medium supplemented with 1% heat-inactivated autologous plasma, 500U/ml IL-4 and 1000 U/ml GM-CSF for 6 days and cryo-preserved. Upon thawing, DC were pulsed with 8 peptides or electroporated with synthetic mRNA encoding 7 antigens. Dendritic cell vaccines were administered by intradermal and subcutaneous biweekly injections for a total of 6 times (= cycle 1). Thereafter vaccination was repeated every 6w until clinical deterioration or patient refusal. Frequencies of blood anti-vaccine CTL were estimated by in vitro restimulation in limiting dilution conditions followed by detection with tetramer assay. Results: Fifteen patients were recruited (9M/6F; median age was 49 y, range 28–81). Seven HLA-A2 patients were treated with peptide pulsed DC (cohort A) and 7 patients (4 HLA-A2 and 3 HLA-A1) with mRNA electroporated DC (cohort B). One patient was sequentially treated with both vaccines. Five patients in cohort A and 3 patients in cohort B completed the first treatment cycle of 6 bi-weekly vaccinations (cycle 1 is ongoing in 3 patients of cohort B). Toxicity was limited to grade 1 or 2 local skin reactions at the vaccine administration sites in all patients. In cohort B one patient qualified for stable disease and 2 other patients with progressive disease displayed regression of individual metastases. A >10-fold increase in CTL precursor frequency was observed in 2 out of 3 patients of cohort A that have been analyzed at present. Conclusions: Vaccination of melanoma patients with peptide pulsed or mRNA electroporated autologous DC vaccines was found to be feasible and safe. Updated results will be presented at the meeting. [Table: see text]