A phase I clinical trial of dendritic cell immunotherapy in HCV-infected individuals.
OBJECTIVE
HCV patients who fail conventional interferon-based therapy have limited treatment options. Dendritic cells are central to the priming and development of antigen-specific CD4(+) and CD8(+) T cell immunity, necessary to elicit effective viral clearance. The aim of the study was to investigate the safety and efficacy of vaccination with autologous dendritic cells loaded with HCV-specific cytotoxic T cell epitopes.


METHODS
We examined the potential of autologous monocyte-derived dendritic cells (MoDC), presenting HCV-specific HLA A2.1-restricted cytotoxic T cell epitopes, to influence the course of infection in six patients who failed conventional therapy. Dendritic cells were loaded and activated ex vivo with lipopeptides. In this phase 1 dose escalation study, all patients received a standard dose of cells by the intradermal route while sequential patients received an increased dose by the intravenous route.


RESULTS
No patient showed a severe adverse reaction although all experienced transient minor side effects. HCV-specific CD8(+) T cell responses were enumerated in PBMC by ELIspot for interferon-gamma. Patients generated de novo responses, not only to peptides presented by the cellular vaccine but also to additional viral epitopes not represented in the lipopeptides, suggestive of epitope spreading. Despite this, no increases in ALT levels were observed. However, the responses were not sustained and failed to influence the viral load, the anti-HCV core antibody response and the level of circulating cytokines.


CONCLUSIONS
Immunotherapy using autologous MoDC pulsed with lipopeptides was safe, but was unable to generate sustained responses or alter the outcome of the infection. Alternative dosing regimens or vaccination routes may need to be considered to achieve therapeutic benefit.
Gowans
Eric J
EJ
Virology Program, Burnet Institute, G.P.O. Box 2284, Melbourne, Vic. 3001, Australia. gowans@burnet.edu.au
Roberts
Stuart
S
Jones
Kathryn
K
Dinatale
Irene
I
Latour
Philippe A
PA
Chua
Brendan
B
Eriksson
Emily M Y
EM
Chin
Ruth
R
Li
Shuo
S
Wall
Dominic M
DM
Sparrow
Rosemary L
RL
Moloney
Jude
J
Loudovaris
Maureen
M
Ffrench
Rosemary
R
Prince
H Miles
HM
Hart
Derek
D
Zeng
Weng
W
Torresi
Joseph
J
Brown
Lorena E
LE
Jackson
David C
DC
D000293:Adolescent; D000328:Adult; D000368:Aged; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014611:Vaccination