« Virus oncolytiques pour l’induction de mort cellulaire immunogène

et l’immunothérapie anti-tumorale »

Virothérapie anti-tumorale : Immunothérapie basée sur

des agents infectieux

Marc GREGOIREmarc.gregoire@inserm.fr

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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FDA agreement on 10/27/2015

T-Vec (Talimogene laherparepvec)

IMLYGICTM

HSV-1 recombinant pour le GM-CSF et délété pour ICP34.5 (facteur de neurovirulence) et ICP47 (protéine inhibant le complexe TAP)

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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JX-594: GM-CSF expressing Oncolytic Vaccinia virus

Breitbach CJ et al. Nature, 2011:Phase I IV injection of JX-594 to patients with metastatic cancer

Tumeurs injectées Tumeurs à distance de l’injection

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40

60

80

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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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;(0(,"4+*%+(0?M+L(,8*#+<*4*(#8&M+CEAE

,vCA

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;(0(,"4+*%+(0?M+L(,8*#+<*4*(#8&M+CEAE ;(0(,"4+*%+(0?M+L(,8*#+<*4*(#8&M+CEAT

* 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