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Oncolytic Virus Lecture

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Oncolytic Virus Lecture

  1. 1. Oncolytic Viruses Targeting Viral Replication and Viral Mediated Lysis to Tumor Cells Tony Reid MD, Ph.D.
  2. 2. Targeting p53
  3. 3. 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
  4. 4. Recurrent/Refractory Head and Neck Cancer Phase II Trial, ONYX-015 Alone Patient Failed Prior Surgery, Radiotherapy, Chemotherapy Day 1 Day 22
  5. 5. 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
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  7. 7. 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
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  9. 9. Response to Onyx-015 4/22/99 5/21/99 6/18/99 9/24/99
  10. 10. Figure 3a 1.50 1.25 1.00 0.75 0.50 0 1 2 3 Months
  11. 11. Figure 3b 1.50 1.25 1.00 0.75 0 1 2 3 Months
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  13. 13. PET Scan 16
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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)
  20. 20. 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)
  21. 21. 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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