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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:

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Dendritic cell-based therapeutic vaccine approaches

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  1. Dendritic cell-based therapeutic vaccine approaches Felipe Garcia 1Hospital Clinic-IDIBAPS-HIVACAT, University of Barcelona. Barcelona.Spain

  2. 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

  3. Therapeutic vaccine: Changing viral set point to a significant level STI ART Pre-ART set point Set point Viral load Time ART STI Pre-ART set point DC Immunotherapy Viral load Transient Definitive Functional cure Set point Time 3

  4. Background

  5. Inactivation Culture Lymphopheresis Autologous virus Inactivated virus ? Monocytes Dendritic cells Immunization Autologous vaccine

  6. 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).

  7. 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

  8. 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 Fig.1 Inclusion criteria: chronic HIV infection >5,000 HIV RNA copies/ml; >500 CD4+ T cells/mm3 HAART STOP 1 HAART STOP 2 HAART NO HAART N=6 s.c. MD-DC injections 1st 2nd 3rd 4th 5th N=12 -246 -90 -78 0 6 12 18 24 30 54 Weeks HIV-pulsed MD-DC Plasmapheresis Unpulsed MD- DC (HIV heat-inactivation and concentration)

  9. Figure 3B Figure 3A Cases: n=12 Figure 3C Figure 3D Controls: n=4

  10. A therapeutic dendritic cell-based vaccine for HIV-1 infection. García F et al J Infect Dis 2011;203:473-8 VIRUS CULTURE 10x9 1st 2nd 3rd doses of 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 48 WEEKS 1st 2nd 3rd doses of non-pulsed MD-DC

  11. VIRAL LOAD RESPONSES IT WAS OBSERVED A MODEST DECREASE OF VL IN VACCINATED PATIENTS

  12. 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)

  13. 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. 16 AGS-004 dosing every 4 weeks 8 weeks 12 weeks Booster Phase ART ART 12 Week STI

  14. CONFIDENTIAL 17 Pre-ART vs. Week 12 of STI Log Change in Viral Load

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

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