[HTML][HTML] Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial

B Escudier, T Dorval, N Chaput, F André… - Journal of translational …, 2005 - Springer
B Escudier, T Dorval, N Chaput, F André, MP Caby, S Novault, C Flament, C Leboulaire…
Journal of translational medicine, 2005Springer
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 …
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 × 1014 molecules) or peptides (10 versus 100 μg/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 × 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.
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