Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial.
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.
Escudier
Bernard
B
Department of Immunotherapy, Institut Gustave Roussy, Villejuif, France. zitvogel@igr.fr.
Dorval
Thierry
T
Chaput
Nathalie
N
André
Fabrice
F
Caby
Marie-Pierre
MP
Novault
Sophie
S
Flament
Caroline
C
Leboulaire
Christophe
C
Borg
Christophe
C
Amigorena
Sebastian
S
Boccaccio
Catherine
C
Bonnerot
Christian
C
Dhellin
Olivier
O
Movassagh
Mojgan
M
Piperno
Sophie
S
Robert
Caroline
C
Serra
Vincent
V
Valente
Nancy
N
Le Pecq
Jean-Bernard
JB
Spatz
Alain
A
Lantz
Olivier
O
Tursz
Thomas
T
Angevin
Eric
E
Zitvogel
Laurence
L
J Immunother. 2003 Sep-Oct;26(5):432-9
12973032
Nat Med. 2001 Jul;7(7):761-5
11433329
Nat Med. 1998 May;4(5):594-600
9585234
J Exp Med. 2001 Oct 15;194(8):1179-86
11602646
Cancer Res. 2001 Sep 1;61(17):6451-8
11522640
J Exp Med. 2004 Jun 7;199(11):1503-11
15173207
J Cell Sci. 2000 Oct;113 Pt 19:3365-74
10984428
J Immunol Methods. 2001 Jan 1;247(1-2):163-74
11150547
Nature. 2003 Sep 25;425(6956):397-402
14508489
J Immunol Methods. 2002 Dec 15;270(2):211-26
12379326
J Transl Med. 2005 Feb 21;3(1):9
15723705
Int J Cancer. 1997 Jun 11;71(6):932-6
9185691
J Immunol. 2004 Feb 15;172(4):2137-46
14764679
J Exp Med. 1996 Mar 1;183(3):1161-72
8642258
Clin Cancer Res. 1999 Feb;5(2):335-41
10037183
J Exp Med. 2002 May 20;195(10):1279-88
12021308
Nat Rev Immunol. 2002 Aug;2(8):569-79
12154376
Cell. 2001 Aug 10;106(3):271-4
11509176
J Immunol. 2004 Feb 15;172(4):2126-36
14764678
Int J Cancer. 1999 Jan 18;80(2):219-30
9935203
J Immunol. 2001 Jun 15;166(12):7309-18
11390481
Int J Cancer. 1994 Mar 15;56(6):826-9
8119772
J Immunol. 2004 May 15;172(10):5957-66
15128777
Int J Cancer. 2001 Nov;94(4):459-73
11745430
Traffic. 2001 Feb;2(2):124-37
11247303
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10290-5
11517302
Nat Immunol. 2002 Dec;3(12):1156-62
12426563
J Immunol. 2000 Sep 15;165(6):3492-6
10975870
J Clin Invest. 1999 Jul;104(2):173-80
10411546
Nat Rev Immunol. 2002 Apr;2(4):227-38
12001994
J Immunother. 2003 Sep-Oct;26(5):440-50
12973033
J Biol Chem. 1998 Aug 7;273(32):20121-7
9685355