1. 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

2. Oncolytic Virotherapy
Most 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 cancers T-VEC: First FDA approved oncolytic virus

3. Adenovirus
Naturally lytic life cycle Many serotypes Broad cell tropism Large amount of nonessential genes Can cause clinical disease- generally self limiting

4. Adenovirus Apoptosis Rb E2F ARF MDM2 p53 Targeted for destruction
Cell Cycle
E1B 55K/
E4 orf6
E1A
Viral Replication

5. Myeloma-Specific Adenovirus
CS1
E1A
Myeloma-specific promoter
ADCE1A
Myeloma Cells
Healthy Cells

6. CS1 is ovrerexpressed in myeloma cell lines
IgG
CS1+ve
Anti-CS1

7. ADCE1A Induced Potent Cell Death in Myeloma Cells 4 Days After infection
Melanoma

8. ADCE1A Induced Potent Cell Death in Primary CD138+ Cells After 4 Days

9. ADCE1A Has No Impact on Normal Bone Microenvironment Cells

10. ADCE1A Induces Cell Death Via an Apoptotic Independent Mechanism

11. ADCE1A in vivo in a high tumour burden model
U266 IV
(1x106)
Treatment IV
(2x/wk)
Bones Flushed
and Analysed
5 weeks
3 weeks
PBS

12. ADCE1A Significantly Reduces Tumour Burden in U266 Xenografts

13. ADCE1A and bortezomib combination therapy prevents cell line recovery

14. ADCE1A and Bortezomib have an additive effect in vitro

15. ADCE1A and Lenalidomide have an additive effect in vitro

16. 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

17. Future Work Test ADCE1A in combination with standard therapies in vivo
Test ADCE1A in dormant/resistant myeloma cells
Optimise viral delivery mechanisms

18. Acknowledgements Dr Simon Tazzyamn Dr Andrew Chantry
Dr Munitta Muthana
Dr Shelly Lawson
Darren Lath
Holly Evans
Jenny Down
Jack Harrision
Beverly King
Dan Holligan