title: Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial.
abstract: BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.
authors.affiliation: Department of Immunotherapy, Institut Gustave Roussy, Villejuif, France. zitvogel@igr.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Thierry
authors.initials: T
authors.lastname: Dorval
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Caby
authors.forename: Sophie
authors.initials: S
authors.lastname: Novault
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Christophe
authors.initials: C
authors.lastname: Leboulaire
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
authors.forename: Catherine
authors.initials: C
authors.lastname: Boccaccio
authors.forename: Christian
authors.initials: C
authors.lastname: Bonnerot
authors.forename: Olivier
authors.initials: O
authors.lastname: Dhellin
authors.forename: Mojgan
authors.initials: M
authors.lastname: Movassagh
authors.forename: Sophie
authors.initials: S
authors.lastname: Piperno
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Vincent
authors.initials: V
authors.lastname: Serra
authors.forename: Nancy
authors.initials: N
authors.lastname: Valente
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Le Pecq
authors.forename: Alain
authors.initials: A
authors.lastname: Spatz
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantz
authors.forename: Thomas
authors.initials: T
authors.lastname: Tursz
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
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