The use of oncolytic virus therapy for myeloma

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

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 2

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

4 Adenovirus Rb E 2 F Cell Cycle E 1 A Viral Replication ARF MDM 2 p 53 Targeted for destruction E 1 B 55 K/ E 4 orf 6 Apoptosis

Myeloma-Specific Adenovirus ADCE 1 A CS 1 Myeloma Cells E 1 A Myeloma-specific promoter Healthy Cells 5

CS 1 is ovrerexpressed in myeloma cell lines Ig. G 6 CS 1+ve Anti-CS 1

ADCE 1 A Induced Potent Cell Death in Myeloma Cells 4 Days After infection Myeloma 7 Melanoma

ADCE 1 A Induced Potent Cell Death in Primary CD 138+ Cells After 4 Days 8

ADCE 1 A Has No Impact on Normal Bone Microenvironment Cells 9

ADCE 1 A Induces Cell Death Via an Apoptotic Independent Mechanism 10

ADCE 1 A in vivo in a high tumour burden model U 266 IV (1 x 106) Treatment IV (2 x/wk) 5 weeks 3 weeks PBS 11 Bones Flushed and Analysed

ADCE 1 A Significantly Reduces Tumour Burden in U 266 Xenografts 12

ADCE 1 A and bortezomib combination therapy prevents cell line recovery 13

ADCE 1 A and Bortezomib have an additive effect in vitro 14

ADCE 1 A and Lenalidomide have an additive effect in vitro 15

Summary ADCE 1 A effectively replicates in, and kills myeloma cells and primary cells Mechanism of cell death is unclear ADCE 1 A shows efficacy in vivo ADCE 1 A stops cell line regrowth in vitro ADCE 1 A shows an additive effect in vitro with standard chemotherapies 16

Future Work Test ADCE 1 A in combination with standard therapies in vivo Test ADCE 1 A in dormant/resistant myeloma cells Optimise viral delivery mechanisms 17

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 18