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.

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• • •

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.