Miss Georgia Stewart Sheffield Myeloma Research Team Department of Oncology and Metabolism Faculty of Medicine Dentistry and Health University of Sheffield UK Most Viruses have a preferential tropism for tumour cells ID: 935563
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Slide1
The use of oncolytic virus therapy for myeloma shows considerable promise in pre-clinical models
Miss Georgia Stewart
Sheffield Myeloma Research Team
Department of Oncology and Metabolism
Faculty of Medicine Dentistry and Health
University of Sheffield, UK
Slide2Most Viruses have a preferential tropism for tumour cells
Intrinsic and extrinsic cell death
Over 48 clinical trials using DNA and RNA viruses in a range of cancersT-VEC: First FDA approved oncolytic virus
2
Oncolytic Virotherapy
Slide3Naturally lytic life cycle
Many serotypes
Broad cell tropism Large amount of nonessential genes Can cause clinical disease- generally self limiting
3
Adenovirus
Slide4Adenovirus
4
Rb
E2F
ARF
MDM2
p53
E1A
Cell Cycle
Viral Replication
E1B 55K/
E4 orf6
Apoptosis
Targeted for
destruction
Slide5Myeloma-Specific Adenovirus
5
Myeloma Cells
Healthy Cells
CS1
E1A
Myeloma-specific promoter
ADCE1A
Slide6CS1 is ovrerexpressed
in myeloma cell lines
6
CS1+ve
IgG
Anti-CS1
Slide7ADCE1A Induced Potent Cell Death in Myeloma Cells 4 Days After infection
7
Myeloma
Melanoma
Slide8ADCE1A Induced Potent Cell Death in Primary CD138+ Cells After 4 Days
8
Slide9ADCE1A Has No Impact on Normal Bone Microenvironment Cells
9
Slide1010
ADCE1A Induces Cell Death Via an Apoptotic Independent Mechanism
Slide11ADCE1A
in vivo
in a high tumour burden model
11
PBS
U266 IV
(1x10
6
)
Treatment IV
(2x/
wk
)
Bones Flushed
and Analysed
5 weeks
3 weeks
Slide12ADCE1A Significantly Reduces Tumour Burden in U266 Xenografts
12
Slide13ADCE1A and
bortezomib
combination therapy prevents cell line recovery
13
Slide14ADCE1A and
Bortezomib
have an additive effect in vitro
14
Slide15ADCE1A and
Lenalidomide
have an additive effect in vitro
15
Slide1616
Summary
ADCE1A effectively replicates in, and kills myeloma cells and primary cells
Mechanism of cell death is unclear
ADCE1A shows efficacy
in vivo
ADCE1A stops cell line regrowth
in vitro
ADCE1A shows an additive effect
in vitro
with standard chemotherapies
Slide1717
Future Work
Test ADCE1A in combination with standard therapies
in vivo
Test ADCE1A in dormant/resistant myeloma cells
Optimise viral delivery mechanisms
Slide1818
Acknowledgements
Dr Simon
TazzyamnDr Andrew ChantryDr
Munitta
Muthana
Dr Shelly Lawson
Darren Lath
Holly Evans Jenny DownJack
HarrisionBeverly King Dan Holligan