Transcript Dendritic cell-based therapeutic vaccine approaches

Dendritic cell-based therapeutic
vaccine approaches
Felipe Garcia
1Hospital Clinic-IDIBAPS-HIVACAT, University of Barcelona.
Barcelona.Spain
Background
• cART is unable to eradicate HIV-1
• cART fails to restore HIV-1-specific T-cell
immune responses
• Alternatives to cART for life:
• Eradication: Berlin patient
• “Functional” cure: fortifying the immune
system= therapeutic vaccines
Therapeutic vaccine:
Changing viral set point to a significant level
12
10
STI
ART
Pre-ART set point
Set point
Viral load
8
6
4
2
0
1
2
3
4
5
6
7
8
9 10 11 12 13 Time
14 15 16 17 18 19 20 21 22 23 24 25 26 27
12
ART
10
STI
Pre-ART set point
Viral load
8
6
DC Immunotherapy
Transient
4
2
Definitive
Set point
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Time
3
Functional cure
Background
GENERACIÓ DE LA VACUNA
ACUN
A
cits i
DCs
Virus
autòle
gs ob
per p
tingut
lasma
s
fères
is
Aïllament dels monòcits i
diferenciació
exVACUNA
vivo a DCs
GENERACIÓ
DE LA
ACUN
A
òcits
i
a DC
s
Pulsin
g dels
DCs a virus i les
lòVlegs
Extracció ud’una
irus a
utòleg
so
per p
mostra de sang
lasma btinguts
fères
is
per a l’obtenció
de DCs
Obten
Aïllament dels monòcits i
ció de
la vac
ex vivo a DCs
terap diferenciació
una
èu
tica
Autologous
virus
GENERACIÓ DE
Inactivation
GENE
RACI
Ó DE
LA VACUNA LA VACUN
A
Inactivated
virus
Lymphopheresis
?
Virus
per
Culture
Aïllam
difere ent dels m
nciac
ió ex onòcits i
vivo
a DC
Monocytes
s
Aïllament dels monòcits i
Extra
diferenciació
cció ex vivo a DCs
d’una
mostr
a
per a de sang
Immunization l’obte
de DC nció
s
Extracció d’una
mostra de sang
per a l’obtenció
de DCs
Autologous
vaccine
Virus autò
per pla
Dendritic cells
Pulsin
g dels
Pulsing
dels vi
DCs a viru
lòlegs
DCs uaulòl
Reported clinical trials
• Overall, 168 patients in 10 clinical trials (60 off cART and 108 on
cART) had received the DCs based vaccine.
• Differences:
• subjects, preparation of DC, HIV-1 antigens, clinical trial design
and immunogical assessment.
• Safety profile has been excellent with only minor local SE
• Results:
• Able to elicit HIV-1 specific immunological responses as
measured by ELISPOT and ICS.
• 4 reported virological responses to immunization (all of them
using autologous virus).
Reported clinical trials
• A non-controlled non-randomized clinical trial
• 18 cART naïve HIV-infected patients
• 3 immunizations with DCs loaded with AT-2
inactivated autologous virus
• VL decreased a median of 0.7 log10 c/ml
• drop of 1 log 10 in the VL for at least 1 year in 8/18
• Induced HIV-1–specific cellular responses.
Lu W et al Nat Med 2004;10:1359-65
Fig.1
THERAPEUTIC IMMUNIZATION WITH
DENDRITIC CELLS LOADED WITH INACTIVATED
AUTOLOGOUS HIV-1 IN CHRONIC HIV-1 INFECTED PATIENTS
García F et al JID 2005;191:1680-1685
Inclusion criteria: chronic HIV infection >5,000 HIV RNA copies/ml; >500 CD4+ T cells/mm3
HAART
STOP 1
HAART
HAART
STOP 2
NO HAART
N=6
s.c. MD-DC injections
1st
2nd
3rd
4th
5th
N=12
-246
-90 -78
Plasmapheresis
(HIV heat-inactivation
and concentration)
0
6
12
18
24
HIV-pulsed MD-DC
30
54 Weeks
Figure 3A
Figure 3B
Cases: n=12
Figure 3C
Figure 3D
Controls: n=4
A therapeutic dendritic cell-based vaccine for HIV-1 infection.
García F et al J Infect Dis 2011;203:473-8
VIRUS
1st 2nd 3rd doses of
CULTURE 10x9 pulsed MD-DC 10x7
DC-HIV (N=12)
Inclusion criteria
1. VL > 10000 c/ml
2. CD4 >450 c/mm3
3. Off cART
Blood sample (120 ml)
for DC generation
DC-PLACEBO
(N=12)
-40
0
2
4
1st 2nd 3rd doses of
non-pulsed MD-DC
48 WEEKS
VIRAL LOAD RESPONSES
IT WAS OBSERVED A MODEST DECREASE OF VL IN VACCINATED PATIENTS
Manufacture of AGS-004
Prepared from DCs generated from autologous PBMCs collected by
leukapheresis.
DCs are matured in culture in the presence of cytokines and then
electroporated with polyadenylated CD40L RNA and autologous RNA amplified
from the subject’s pre-ART plasma HIV sample (Gag, Vpr, Rev, Nef)
HIV Phase 2a Study Design:
CTN 239
AGS-004-001 is a single-arm, open-label, Phase 2a study of
the safety and antiviral activity of AGS-004. Subjects
receive 4 doses of AGS-004 while on ART and then
interrupt antiretroviral drug treatment while receiving study
drug.
AGS-004 dosing every 4 weeks
8 weeks
ART
12 Week STI
12 weeks
Booster Phase
ART
16
Pre-ART vs. Week 12 of STI Log Change in Viral Load
2.00
1.00
0.00
Log Change in VL
-1.00
-2.00
-3.00
-4.00
-5.00
-6.00
•
•
•
CONFIDENTIAL
17
Ongoing clinical trials
• 7 ongoing clinical trials with DC vaccination.
• On cART and in 4 trials there will be a cART STI
• Clinical trial design, 5 uncontrolled and preliminary, 2
placebo controlled multicenter studies.
• Immunogen:
• 4 DCs electroporated with mRNA (1 encoding
autologous HIV)
• 2 whole inactivated virus (1 chemically and 1 heat
inactivated)
• 1 peptide pulsed DC.
CONCLUSIONS
 Marked differences in
 type of subjects,
 preparation of DC
 HIV antigen
 clinical trial design
 immunogical assessment.
 The safety profile has been excellent with only
minor local side effects reported.
CONCLUSIONS
 Able to elicit HIV-1 specific immunological
responses as measured by ELISPOT and ICS.
 Only four of these studies reported virological
responses to immunization.
 A first meeting on DC-based immunotherapy of
HIV-1-infected individuals has been hold.
 Recommendations will be given when more
randomized studies will be completed.
ACKNOWLEDGMENTS
• Bernard Macatangay, Charles Rinaldo, Sharon Riddler University of Pittsburgh
• Geoffrey W. Stone, HIV Program,, University of Miami
• Anders Fomsgaard, Statens Serum Institut, Copenhagen, Denmark.
• Jean-Pierre Routy, McGill University Health Centre, McGill University, Montreal
• Rafick P Sekaly, Oregon Health and Science University, Florida.
• Winni De Haes, Guido Vanham, Institute of Tropical Medicine Antwerp Belgium
• Joeri Aerts, Sabine Allard, Patrick Lacor, Kris Thielemans, Medical School of the Vrije
Universiteit Brussel , Brussels
• Rob Gruters, Albert Osterhaus. Department of Virology, Erasmus MC, Rotterdam
• Felipe García, Teresa Gallart; Nuria Climent, Montserrat Plana, Cristina Gil, Agathe
León, Josep M Gatell, Bonaventura Clotet, Javier Martínez-Picado, Christian Brander.
HIVACAT, IRSICAIXA and Hospital Clinic. Barcelona. Spain
ACKNOWLEDGMENTS
DCV2/MANON07-ORVACS study group:
Hospital Carlos III, Madrid: JM Benito, MO López Vázquez de la Torre, C Ballesteros Blanco.
HIVACAT-Hospital Clinic, Barcelona: T Gallart , F García, N Climent, C Gil, M Plana, A León,
L Alós, M Caballero, A Díaz, F Lomeña, JM Gatell.
HIVACAT-Hospital Germans Trias I Pujol. Badalona: J Romeu, M Bofill, C Brander, N Izquierdo, J
Dalmau, J Martinez-Picado, B Clotet.
Hospital Gregorio Marañón, Madrid: L Chonco, N Wever, M Pion, MJ Serramía, M Relloso,
P
Ortega, J Mata, R Gómez, MÁ Muñoz-Fernández.
Hospital Universitario Reina Sofía, Córdoba: J Peña, R González, M Frias, B Manzanares, L Castro.
Instituto de Salud Carlos III, Madrid: N González, J Alcamí, MT Perez, J Garcia, LM Bedoya.
 INSERM U943 et UPMC Univ Paris. Hôpital Pitié-Salpêtrière, Paris: L Assoumou, D Costagliola
 AIDS Vaccine Program, SAIC-Frederick, Inc., Frederick, USA J Lifson
 UPMC Univ. Paris 06, INSERM UMR-S 945, Hôpital Pitié-Salpêtrière, Paris, France: B Autran.