4. Unique Mechanism of Action
• Cell lysis
• Immune recognition of
viral particles tags
tumor cells as foreign
• Presentation of tumor
antigens in the context
of an active infection.
• Sensitize to additional
chemotherapy
• Down regulate inhibitory
immune responses
5. Recurrent/Refractory Head and Neck Cancer
Phase II Trial, ONYX-015 Alone
Patient Failed Prior Surgery, Radiotherapy, Chemotherapy
Day 1 Day 22
8. 39 year old male with colon cancer
metastatic to the liver. He had failed
treatment with 3 prior treatment regimens.
He was started on treatment with an
oncolytic adenovirus, Onyx-015.
8
17. Comparison of CT and PET response
• 51-year-old male with primary
gastrointestinal stromal tumors of
colon and recurrent peritoneal
metastases. Pretreatment
computed tomography (CT) scan
shows (A) a relatively low-density
peritoneal mass (42 Hounsfield
units [HU]) ( ) corresponding to
(B) a lesion with markedly
increased glucose uptake ( ) on
positron emission tomography
using [18F]fluorodeoxyglucose
(FDG-PET). At 2 months after
treatment, (C) the mass ( ) has
become larger, however, the CT
density has decreased (30 HU),
(D) with no appreciable glucose
uptake ( ) on FDG-PET,
corresponding to clinical
improvement. (Reprinted with
permission.11)
17
18.
19. Hepatic Toxicity
• Minimal toxicity despite
arterial infusion of
2x10e12 particles
• Transient changes in
hepatic function are
mild, early and only with
repeated infusion
• May be related to
cytokine induction
• CAR localized to
intercellular spaces
20. Targeted & Armed Biotherapeutic Products:
Amplification, spread and cell lysis within human tumors
24 hours time-lapse photos: self-amplification leads to tumor
Stanford Bio-Imaging Center: S Thorne
Jennerex Biotherapeutic Labeled Green
21. JX-594 Design: Multi-Targeted, Multi-Mechanistic
Targets multiple cancer pathways: E2F/Cell cycle, EGFR/ras, IFN response
• Backbone: Wyeth > 10 Million safety database
• Natural targeting: common genetic pathways in cancer
– Loss of IFN response pathway: IFN-binding/ inhibition inactive (B18R-)
– Activated EGF-R / ras pathway
• Engineered targeting: deletion of viral TK gene
– Thymidine kinase deleted (deficient nucleotide pools)
– Cellular TK over-expressed in cancer (cell cycle / E2F activation)
• Arming: GM-CSF (synth E/L promoter)
– Tumor-specific CTL
– Tumor vascular shutdown
22. Jennerex Products Attack Tumors
by Multiple Mechanisms
1. Infection of cancer
cells
– Cell lysis
– Virus amplification &
spread within tumor
2. Shutdown of tumor
blood flow
– Uninfected tumor cell death
3. Stimulation of immune
response
– Rejection of tumor by host
immune cells
9/1/2009 22
23. Efficient IV Delivery of JX-594
Prototype to Tumors:
High cancer-selectivity, reproducibility; multiple species, cancers
24h post-I.V. injection 48h post-I.V. injection
primary
tumor
lymph node
metastasis
IV tail vein injection
•I.V. TK(-)/Luc(+) (108 pfu)
•BalbC immunocompetent mice
•s.c. 4T1 mammary tumors
(Thorne, unpublished)
24. Pharmacokinetics: Unique Replication-Dependent PK
Input, clearance followed by replication waves
Input
Clearance Replication waves
Cohort 3
Cohort 1
0.25 3 5 8 15 22
days post-treatment
9/1/2009 24
(Park et al Lancet Oncol 2008)
25. Liver Cancer Tumor in Neck: Eradication by JX-594
Treatment feasible in different locations, sequential re-treatment over time
66 y.o. man - metastatic liver cancer
Cancer progression despite 5 prior therapies
Major tumor response in liver
New tumor in neck: re-treatment tumor eradication; durable > 6 months
Survival 11+ months
baseline
4 cycles
25
