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
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ART
ART
Pre-ART set point
Pre-ART set point
STI
STI
DC Immunotherapy
Set point
Set point
Therapeutic vaccine:Changing viral set point to a significant level
Time
Time
Vira
l loa
dVi
ral l
oad
3
Transient
Definitive
Functional cure
BackgroundGENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció
de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció
de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
Dendritic cells
Autologous virus Inactivation
Lymphopheresis Culture
Autologous vaccine
GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció
de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
Monocytes
Immunization
Inactivated virus
?
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
-246 -90 -78 0 6 12 18 24 30 54 Weeks U
npul
sed
MD
- DC
HAART
Inclusion criteria: chronic HIV infection >5,000 HIV RNA copies/ml; >500 CD4+ T cells/mm3
1st 2nd 3rd 4th 5th
HAART STOP 1
PlasmapheresisHIV-pulsed MD-DC
s.c. MD-DC injections
HAART STOP 2
N=6
N=12
NO HAART
(HIV heat-inactivation and concentration)
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
Figure 3DFigure 3C
Figure 3BFigure 3A
Cases: n=12
Controls: n=4
Inclusion criteria1. VL > 10000 c/ml2. CD4 >450 c/mm3
3. Off cART
DC-HIV (N=12)
-40 0 2 4 48 WEEKS
1st 2nd 3rd doses of pulsed MD-DC 10x7
VIRUS CULTURE 10x9
DC-PLACEBO (N=12)
Blood sample (120 ml) for DC generation
1st 2nd 3rd doses of non-pulsed MD-DC
A therapeutic dendritic cell-based vaccine for HIV-1 infection. García F et al J Infect Dis 2011;203:473-8
VIRAL LOAD RESPONSES
IT WAS OBSERVED A MODEST DECREASE OF VL IN VACCINATED PATIENTS
Manufacture of AGS-004Prepared 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 dosing every 4 weeks8 weeks 12 weeks
ART 12 Week STI Booster Phase ART
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.
16
• • •
Pre-ART vs. Week 12 of STI Log Change in Viral Load
-6.00
-5.00
-4.00
-3.00
-2.00
-1.00
0.00
1.00
2.00
Log
Chan
ge in
VL
17CONFIDENTIAL
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.