Oncolytic Virus Lecture

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 Cancer Phase II Trial, ONYX-015 Alone Patient Failed Prior Surgery, Radiotherapy, Chemotherapy Day 1 Day 22

Fig. 4 (A) BEAS-2B (B) PANC-1 100000 10000 Ad5 10000 dl1520 1000 1000 100 100 10 10 1 37oC 40oC 39.5oC 1 37oC o 40 C 39.5oC (C) Calu-6 (D) LNCaP 100000 100000 10000 10000 1000 1000 100 100 10 10 1 1 o o 37 C 39.5C 40 oC 37oC 39.5oC 40 oC

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

Response to Onyx-015 4/22/99 5/21/99 6/18/99 9/24/99

Figure 3a 1.50 1.25 1.00 0.75 0.50 0 1 2 3 Months

Figure 3b 1.50 1.25 1.00 0.75 0 1 2 3 Months

PET Scan 16

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

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 24 hours time-lapse photos: self-amplification leads to tumor Stanford Bio-Imaging Center: S Thorne Jennerex Biotherapeutic Labeled Green

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

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

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)

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)

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

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Oncolytic Virus Lecture

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