Oncolytic Viruses

Targeting Viral Replication and Viral Mediated Lysis to Tumor Cells

Tony Reid MD, Ph.D.

Targeting p53

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

Recurrent/Refractory Head and Neck CancerRecurrent/Refractory Head and Neck CancerPhase II Trial, ONYXPhase II Trial, ONYX--015 Alone015 Alone

Patient Failed Prior Surgery, Radiotherapy, ChemotherapyPatient Failed Prior Surgery, Radiotherapy, Chemotherapy

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Fig. 4 (A) BEAS-2B

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37oC 40oC1

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(C) Calu-6

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(D) LNCaP

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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.

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Response to Onyx-015

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9/24/99

Figure 3a

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Figure 3b

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PET Scan

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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)

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

Targeted & Armed Biotherapeutic Products:Amplification, spread and cell lysis within human tumors

Stanford Bio-Imaging Center: S ThorneJennerex Biotherapeutic Labeled Green

24 hours time-lapse photos: self-amplification leads to tumor

JX-594 Design: Multi-Targeted, Multi-MechanisticTargets 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

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

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Jennerex Products Attack Tumors by Multiple Mechanisms

48h post-I.V. injection

primarytumor

lymph nodemetastasis

•I.V. TK(-)/Luc(+) (108 pfu) •BalbC immunocompetent mice•s.c. 4T1 mammary tumors

(Thorne, unpublished)

24h post-I.V. injection

Efficient IV Delivery of JX-594 Prototype to Tumors:

High cancer-selectivity, reproducibility; multiple species, cancers

IV tail vein injection

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Pharmacokinetics: Unique Replication-Dependent PKInput, clearance followed by replication waves

22158530.25

days post-treatment

Input

Clearance Replication waves

Cohort 3

Cohort 1

(Park et al Lancet Oncol 2008)

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baseline

4 cycles

Liver Cancer Tumor in Neck: Eradication by JX-594Treatment feasible in different locations, sequential re-treatment over time

66 y.o. man - metastatic liver cancerCancer progression despite 5 prior therapiesMajor tumor response in liverNew tumor in neck: re-treatment tumor eradication; durable > 6 monthsSurvival 11+ months

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