Virothérapie anti-tumorale : Immunothérapie basée sur des ... · 1924 2014 Vous avez dit virus...
Transcript of Virothérapie anti-tumorale : Immunothérapie basée sur des ... · 1924 2014 Vous avez dit virus...
« Virus oncolytiques pour l’induction de mort cellulaire immunogène
et l’immunothérapie anti-tumorale »
Virothérapie anti-tumorale : Immunothérapie basée sur
des agents infectieux
Marc [email protected]
1924 2014
Vous avez dit virus oncolytiques ?
En 1924 William Coley, chirurgien des os et cancérologue, observe le cas d'un patient qui souffre à la fois d'un cancer gravissime, le sarcome, et d'une infection cutanée, la scarlatine. Mais, au sortir de son épisode de scarlatine, le malade guérit de son sarcome, sans traitement spécifique, et il ne rechute plus jamais. Le docteur Coley en déduit que l'infection par le streptocoque, la bactérie de la scarlatine, a déclenché quelque chose qui a permis de détruire les cellules cancéreuses, soit directement, soit par une stimulation de son immunité. Nature, 2013, 504 (S4-S5)
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Virus MarabaVirus de la rougeole
Virus des oreillonsNewcastle Disease Virus
Poliovirus Reovirus
RétrovirusSénécavirus
Virus de la Stomatite Vésiculaire
AdénovirusHerpèsvirusParvovirus
Virus de la vaccine
Virus à ADN
Virus à ARN
D’après Russell SJ et al. Nat Biotechnol. 2012 ; 10;30(7):658-70
Virothérapie anti-tumorale
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OncoVEXGM-CSF: Oncolytic Herpes Simplex Virus type I (HSV-1)
Effets cliniques à distance du point d’injection
Senzer NN et al. J Clin Oncol. 2009 Dec 1;27(34):5763-71
JX-594 Pexa-Vec (Pexastimogene devacirepvec)
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Conclusions
PreferedInfection
Limited infection
MV
Tumor cells(CD46high)
Healthy cells(CD46low)
Apoptosis
Immature Mo-DC
Immature plasmacytoid DC
MV-infectedTumor cells
Mature Mo-DC
Mature plasmacytoid DC
TAAPAMP?DAMP(HSP70, gp96)
TAAPAMP(MV Single-strand RNA)DAMP?
Phagocytosis
Phagocytosis
Maturation
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-6IL-8)
Blood myeloid DC ? CD1c+ DC ? CD141+ DC ?
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;(0(,"4+*%+(0?M+L(,8*#+<*4*(#8&M+CEAT
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* On-going clinical phase I/II clinical trials for 5 cancers (ovarian, mesothelioma, glioma, HNSCC, myeloma)
* Published clinical trials: -Ovarian: 21 MV seropositive patients refractory to two lines of chemotherapy (Taxol, platine), intraperitoneal injections: stabilization of disease for 14 patients with doubling of the overall median survival (Galanis E et al, cancer research, 2010). - Ovarian: 16 MV seropositive patients, intraperitoneal injections: overall median survival reach 26 months instead of 12months in uninjected patients (Galanis E et al, cancer research, 2015). - Multiple myeloma: 2 MV seronegative patients, intravenous injection: two complete responses (one relapsed and the other was still alive six months after the CR induced by the treatment) (Russell SJ et al, Mayo Clin Proc, 2014).
Clinical trials performed with patents for USA exclusively: Drs. Russell SJ and Galanis E (Mayo clinic, Rochester, USA)
Clinical trials
Conclusions
Les virus oncolytiques constituent un classe de nouveaux agent thérapeutiques
Sûrs Peu d’effets secondaires
Sécurité démontrée en essais cliniques
Efficaces Traitement de cancers agressifs
Activation de réponses immunitaires
CRCNA – Equipe 4Marc GRÉGOIRE Christophe BLANQUART Nicolas BOISGERAULT Jean-François FONTENEAU Daniel POULIQUEN
Anne-Claire BRANCHU Delphine COULAIS Virginie DEHAMESophie DESHAYES Nina GUYON
Carole ACHARD Ferdaous ALLAGUI Douae BENSAID Thibaut BLONDY Tiphaine DELAUNAY Camille LINOT Joëlle NADER Mustapha TALATIZI
Frédéric TANGY Chantal COMBREDET