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Immunoadjuvant Properties of Oncolytic Schwarz Measles Virus Dr Jean-François Fonteneau Institut de Recherche en Santé de l’Université de Nantes INSERM.

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Presentation on theme: "Immunoadjuvant Properties of Oncolytic Schwarz Measles Virus Dr Jean-François Fonteneau Institut de Recherche en Santé de l’Université de Nantes INSERM."— Presentation transcript:

1 Immunoadjuvant Properties of Oncolytic Schwarz Measles Virus Dr Jean-François Fonteneau Institut de Recherche en Santé de l’Université de Nantes INSERM UMR892, CNRS UMR6299 Nantes, France

2 Anti-tumor Virotherapy using oncolytic virus Oncolytic virus Ideal replicating oncolytic virus: (Russell SJ, Nature biotechnol, 2012 Vacchelli E et al, Oncoimmunology, 2013) - Kills efficiently tumor cells (apoptosis) Infection Healthy cells - No toxicity (genetically stable, minor side effects) - High viral concentration production capability - Infects exclusively or preferentially tumor cells Tumor cells Infection apoptosis - Induction or stimulation of an anti-tumor immune response. Activation of the immune system

3 Measles virus vaccine (MV) based anti-tumoral virotherapy Measles virus vaccine, Schwarz strain (MV): Dr Frédéric Tangy (Viral genomics and Vaccination laboratory, Pasteur Institut, Paris) - Attenuated replicating vaccine strain of measles virus: Schwarz (MMR vaccine) - Targets CD46, complement regulatory protein (wt MV targets CD150/SLAM) - CD46 is expressed at low level by healthy cells - CD46 is often found overexpressed on tumor cells - Spontaneously oncolytic: - Lymphoma, glioma, breast, ovary, prostate … (Russell SJ, Mayo Clinic, USA) - MPM, colon and lung adenocarcinoma (Gauvrit A et al, Cancer Research, 2008; Boisgerault N et al, Biomed Res Int, 2013) Protéine L Protéine de Fusion (F) Hémagglutinine (H) Protéine de Matrice (M) Double membrane lipidique Phosphoprotéine (P) ARN + Nucléoprotéine (N) - Enveloped, non-segmented, negative-sense, single-stranded RNA (ssRNA) paramyxovirus of the genus Morbillivirus Guillerme JB et al, Biology, antiviral pathway defects are often found in tumor cells

4 Video : MV infection of meso13 by MV-eGFP (enhanced green fluorescent protein) MV infection of Malignant Pleural Mesothelioma tumor cells

5 Limited MV infection of healthy mesothelial cells Video : healthy mesothelial cells exposed to MV-eGFP

6 Cross presentation to CD8+ T Lymphocytes (CTL)? Tumor cells Immature DC Apoptosis MV Activation of the immune system by MV infected tumor cells ? Danger signals DAMPs ? PAMPs ? Mature DC ? Myeloid DC? Plasmacytoid DC?

7 CD83 CD86 IL-10 IL-12p70 Mo-DC activation Activation of monocyte derived DC (Mo-DC) and tumor antigen cross-priming by MV infected tumor cells Gauvrit et al, Cancer Research, 2008 Tumor antigen cross-priming

8 Expression of TLR7 et TLR9 => specialized in recognition of viral nucleic acids MV ARNsb IFN-  Production and tumor antigen cross-presentation by pDC exposed to MV infected tumor cells? Plasmacytoid Dendritic Cells (pDC) Produce huge quantities of Type I IFN (-  and –  ) in response to virus Antigen cross presentation in human: HIV (Hoeffel, G,.Immunity, 2007) (Crozat, K., J Exp Med, 2010) Influenza (Lui, G., PLoS One, 2009) Antigen cross presentation in mice: Cross-tolérance (Goubier, A., Dubois, B., Immunity, 2008) OVA (Mouries, J., Blood, 2008) One of the target of imiquimod (R837, TLR7 ligand) in the treatment of basal cell carcinoma with Aldara.

9 pDC are not infected by Schwarz MV Video : pDC exposed to MV-eGFP

10 MV infected tumor cells induce maturation of plasmacytoid DC Meso13 MV Meso13 UV IL3 R848 MV IL-3 + MV CD83 IL3 MV MV+IL3 R848 M18 MV M18 UV Meso13 MV Meso13 UV A549 MV A549 UV ** *** ** *** % Positive Cells CD40 IL3 MV MV+IL3 R848 M18 MV M18 UV Meso13 MV Meso13 UV A549 MV A549 UV * R-MFI CD86 IL3 MV MV+IL3 R848 M18 MV M18 UV Meso13 MV Meso13 UV A549 MV A549 UV * R-MFI

11 MV infected tumor cells are internalized by plasmacytoid DC 4°C37°C MV UV M18 MV UV A549 37° C 4°C PKH67 BDCA-4 PKH67 HLA-DR pDCMo-DC HLA-DR Alexa568PKH-67MERGE pDC + M18 MV pDC + A549 MV

12 MV activates pDC IFN-  production by TLR7 IRS661: TLR7inhibitor (TLR-9) pDC IFN-α (ng/ml)

13 MV probably activates pDC via TLR7 in early endosome CpG-A (TLR9) Kerkmann M et al, J Immunol, 2003 CpG-B (TLR9) -> High IFN-  -> Low IFN-  -> Low inflammatory molecules secretion (IL-8) -> High inflammatory molecules secretion (IL-8) -> Low costimulation (CD80, CD86) -> High costimulation (CD80, CD86) Early endosome Late endosome Honda K et al, Nature, 2005 Guiducci C et al, J Exp Med, 2006 Sadaka C et al, Blood, 2009 Kubo-Murai M et al, Blood, 2008 IRF7 pathway NF-  B pathway HIV (TLR7)R848 (TLR7/TLR8) CpG-B (TLR9) O’brien M et al, J Clin Invest, 2011 MV (TLR7) R848 (TLR7/TLR8) Guillerme JB et al, clin cancer Res, 2013

14 NYESO-1 cross-presentation by pDC exposed to MV infected tumor cells M18 : HLA-A*0201-, NYESO-1+ A549 : HLA-A*0201-, NYESO-1- pDC : HLA-A*0201+, NYESO-1- M : HLA-A*0201/NYESO-1( ) specific CD8+ T cell clone

15 NYESO-1 cross-presentation by pDC exposed to MV infected tumor cells

16 NYESO-1 cross-presentation by pDC and Mo-DC exposed to MV infected tumor cells HLA-A*0201 neg /NY-ESO-1 pos Mo-DCpDC Ø NYESO-1 [ ] (10µM) M18MV M18 UV IFN-y -y 0.6% 11.7% 68% 0.16% 0.3% 8.15% 79.6% 0.4% CD8 LT only Mo-DCi Mo-DCm + 0,1µM NY-ESO-1 Mo-DC + M18MV Mo-DC + M18UV % of IFN  + T CD8+ cells Mo - DC Cross-presentation pDC cross-presentation

17 0,5 Mo-DC 95,1 Mo-DC + pep 1µM M18 MV M18 UV Mo-DC Mo-DC + IFN-γ + TNF-α Mo-DC + R848 10,022,77,0 0,52,20,9 M18 MV M18 UV 1,24,91,3 0,52,30,7 (-)IFN-γ + TNF-αR848 % CD8 + /IFNγ + cells Mo-DC (-) R848 IFN-γ TNF-  (-) R848 (-) R848 (-) R848 M18 MVM18 UVM18 MVM18 UV (+) Mo-DC(-) Mo-DC IFN-γ TNF-  Deauvieau F et al, Int J Cancer, 2014 NYESO-1 cross-presentation by Mo-DC is increased by TNF-  /IFN- 

18 Conclusions Prefered Infection Limited infection MV Tumor cells (CD46 high ) Healthy cells (CD46 low ) Apoptosis Immature Mo-DC Immature plasmacytoid DC MV-infected Tumor cells Mature Mo-DC Mature plasmacytoid DC TAA PAMP? DAMP (HSP70, gp96) TAA PAMP (MV Single-strand RNA) DAMP? Phagocytosis Maturation ->Cross-priming of TAA-specific CD8+ T cell response ->Cross-presentation of TAA to specific CD8+ T cells Cross-priming ? ->Production of a large quantity of IFN-  Gauvrit A et al, Cancer Research, 2008 Guillerme JB et al, Clinical Cancer Research, 2013 Donnelly OG et al, Gene Ther, 2013 (IFN- , IFN- , HMGB1, IL-6 IL-8) Blood myeloid DC ? CD1c+ DC ? CD141+ DC ?

19 Plateforme de dévelopement et de transfert à la clinique (CHU Nantes) : Delphine Coulais, ingénieur Clarisse Panterne, ingénieur Service de pneumologie du CHU de Nantes Laurent Cellerin, Christine Sagan Antoine Magnan Service de pneumologie du CHU de Lille Arnaud Scherpereel Institut Pasteur, Viral genomics and Vaccination laboratory Frédéric Tangy Mariana Mesel-Lemoine Collaborations Centre de Recherche en cancérologie de Lyon Jenny Valladeau Christophe Caux Marc Grégoire, INSERM Christophe Blanquart, CNRS Daniel Pouliquen, INSERM Jean-François Fonteneau, INSERM Nicolas Boisgerault Jean-Baptiste Guillerme Carole Achard, Ferdaous Allagui Iza Denis Clarisse Panterne Sophie Deshayes Team (Inserm U892,Nantes) Funding


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