EricQ_Curie June 2016

25 Pages·2016·3.26 MB·English

Immunotherapies for cancer and infectious diseases
MOVING TOWARD MULTI-FUNCTIONALITY IN
ONCOLYTIC VIROTHERAPY
Eric Quéméneur
Precision medicine – Crowbiomeeting @Curie
June 10, 2016
Oncolytic viruses, an emerging therapeutic class
Brit. J Cancer, Jan. 2016
"oncolytic virus"
in PubMed
Nature ReviewsDrug Disc,
Sept. 2015 350
300
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Nature ReviewsCancer,
a 250
Aug. 2014 p

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Trends in Cancer, Dec. 2015
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Nature ReviewsCancer, Jan. 2009
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1950 1970 1990 2010 2030
Year
FrontiersImmunol. Feb. 2014
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Oncolytic Vaccinia Viruses (oVV)
Sophisticated war machines acting at all levels, locally and systemically
• Selective replication in tumor cells
Cellular
- Healthy cells can be infected but are naturally
protected against viral replication
- Tumor physiology favors viral infection and
replication, since cancer-associated pathways
immune evasion do inhibit host antiviral responses
• Lysis of tumor cells, associated with immunogenic
Tissular
cell death (release of DAMP, HMGB1, Ecto-CRT) and
(tumor µ-environment)
subsequent release of TAA / neoantigens
• Self-amplifying therapy
• Local expression of transgene product (cytokine, enzyme, antibody)
• Interference with cellular cross-talks between components of TME
(e.g. CAFs and vascular endothelium for angiogenesis, CAFs and
cancer cells)
• OVs stimulate infiltration and homing of immune cells
• Damage to the endothelial cells and vasculature
Organism
• Innate and adaptive immune response
• Viral systemic spread to metastasis
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Oncolytic viruses in clinical development
Approved products
• Imlygic / T-vec (Amgen) ; oHSV armed with GM-CSF ; Approved for melanoma (IT) in USA and EU
• Oncorine / H101 (Sunway biotech) ; oAdV (no arming) ; Approved for H&N in China
• Rigvir (IVC) ; ECHO-7 enterovirus ; Appr. for melanoma in Latvia and Georgia
Phase 2-3 clinical trials
• CG0070 (Cold Genesys) ; oAdV armed with GM-CSF
• Onco-102 (Targovax) ; oAdV armed with GM-CSF and RGD
• DNX-2401 (DNAtrix) ; oAdV armed with RGD
• PexaVec / TG6006 (Sillajen, Transgene) ; oVV (TK-) armed with GM-CSF
• GL-ONC1 (Genelux) ; oVV (TK-)
• HF10 (Takara Bio) ; oHSV
• Seprehvir (Virttu Biol.) ; oHSV
• Reolysin (Oncolytics biotech) ; reovirus
• SVV-001 (Neotropix) ; Seneca Valley Virus
• Cavatak (Viralytics) ; Cocksackie virus
• TOCA-511 (Tocagen) ; retrovirus armed with yCD
Starting clinical devpt
• TG6002 (Transgene) ; oVV(TK-RR-) armed with Fcu1
• MeV-SCD (UKT) ; oMV armed with Fcu1
• MV-NIS ; Measles armed with NIS
Etc.
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Direct imaging of viral oncolysis at the cellular level
e.g. Meso 173 (mesothelioma cell line) after infection (MOI 0.1) by VV[TK-RR-]-eGFP
Collaboration avec CRCNA
(Centre de Recherche en Cancérologie Nantes-Angers)
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TG6002 – Safety profile
Tumor-selective replication
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Hep G2 Human hepatocytes
H. Tumor cells H. Normal cells
The TK-RR- double deleted oVV is largely replication defective in normal cells and
thus displays an exceptional therapeutic index compared to other oncolytic viruses.
6
Biodistribution study
VV TK-RR-/Luciferase
WR
MiaPaca2 (pancreas), i.p.
Virus administration (1 injection i.v.) at D40 post-tumor implantation
Day 4 Day 7 Day 11
Selective replication in the tumor, long lasting effect, limited virus spread in
the absence of metastasis
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Biodistribution in immunocompetent models
LoVo cells (CRC) s.c. in balb/c mice
• TG6002 ESSENTIALLY DISTRIBUTES IN THE TUMOR
• NO RETENTION IN OTHER ORGANS, EXCEPT VERY TRANSIENTLY IN OVARIES
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Activity of TG6002 : Tumor growth control
Human tumor lines in nude mice
HS-746T (stomach), s.c.
OE19 (oesophageal), s.c.
N=12
N=12
Placebo
Placebo + 5-FC
TG6002
TG6002 + 5-FC
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Activity of TG6002 : Survival
Human tumor lines in nude mice
SKOV (ovarian), i.p.
U-87MG (glioblastome), intracerebral
N=8
N=12
Placebo
Placebo + 5-FC
TG6002
TG6002 + 5-FC
10