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

Journal of Translational Medicine

Laurence Zitvogel⁹  Eric Angevin⁹  Thomas Tursz⁹  Olivier Lantz⁷  Alain Spatz³  Jean-Bernard Le Pecq⁴  Nancy Valente⁴  Vincent Serra¹  Caroline Robert²  Sophie Piperno⁵  Mojgan Movassagh⁹  Olivier Dhellin¹  Christian Bonnerot⁷  Catherine Boccaccio⁶  Sebastian Amigorena⁷  Christophe Borg⁹  Christophe Leboulaire⁹  Caroline Flament⁹  Sophie Novault⁹  Marie-Pierre Caby⁷  Fabrice André⁹  Nathalie Chaput⁹  Thierry Dorval⁵  Bernard Escudier⁸ 

[1] Anosys S.A, Evry, France;Department of Dermatology, Institut Gustave Roussy, Villejuif, France;Department of Pathology, Institut Gustave Roussy, Villejuif, France;Anosys Inc, Menlo Park, California, USA;Department of Clinical Oncology, Institut Curie, Paris, France;Cell Therapy Unit, Institut Gustave Roussy, Villejuif, France;U520INSERM, Institut Curie, Paris, France;Department of Immunotherapy, Institut Gustave Roussy, Villejuif, France;ERM0208 INSERM, Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France

关键词: immunotherapy;    cancer vaccine;    phase I trial;    dendritic cells;    exosomes;   

Others  :  1208506
DOI  :  10.1186/1479-5876-3-10

 received in 2004-12-31, accepted in 2005-03-02,  发布年份 2005

【 摘 要 】

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.

【 授权许可】

   
2005 Escudier et al; licensee BioMed Central Ltd.

【 图 表 】

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