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Pre – clinical studies on oncolytic HSV1716 in hepatocellular carcinoma. Lynne Braidwood

Pre – clinical studies on oncolytic HSV1716 in hepatocellular carcinoma. Lynne Braidwood . Origin of HSV1716 ( Seprehvir ). Herpes simplex virus type 1 (HSV1) is a common human virus that naturally infects most of the population.

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Pre – clinical studies on oncolytic HSV1716 in hepatocellular carcinoma. Lynne Braidwood

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  1. Pre – clinical studies on oncolytic HSV1716 in hepatocellular carcinoma. Lynne Braidwood

  2. Origin of HSV1716 (Seprehvir) • Herpes simplex virus type 1 (HSV1) is a common human virus that naturally infects most of the population. • Our product HSV1716 is a modified version of HSV1 that lacks both copies of a single gene encoding a protein (ICP34.5) which is essential for virus replication and virulence in normal cells and tissues • In cancer cells, the requirement for ICP34.5 is negated by proteins and cellular pathways that are active only in cancer cells resulting in specific lysis of the tumour cells, whereas normal cells are unaffected.

  3. Tumour selective mode of action

  4. Clinical Studies Overview • Ongoing study in paediatric/young adults (Non-CNS tumours, 5 patients) • Ongoing study in malignant pleural mesothelioma (2 patients) • Completed safety / proof of concept studies in 72 patients • 47 patients in brain tumour studies (4 studies) • 5 patients in advanced metastatic melanoma study • 20 patients in oral squamous cell carcinoma study • No toxicity attributable to HSV1716 experienced by any patient • Proof of Principle that HSV1716 virus replicates in tumours

  5. Hepatocellular carcinoma(HCC) • Global health problem- HCC is the most common solid organ malignancy • 5th most common malignancy globally • 3rd most common cause of death due to cancer • Increasing incidence (HCC rates tripled in US • between 1975 and 2005) • 662,000 deaths annually • c1,500 deaths a year in the UK • Treatment • Surgery • Chemotherapy (eg doxorubicin) • Dismal prognosis • 90% of patients dead within six months • almost all patients dead with one year of diagnosis

  6. HSV1716 synergizes with doxorubicin in vitro • Doxorubicin – used frequently as single agent in advanced HCC and is frequently an active chemotherapeutic in TACE. • HSV1716 in combination with doxorubicin assessed in vitro in HepG2-luc and HuH7 • Chou-Talalay analysis identifies strong synergy signals in both HCC cell lines • Potential for enhanced efficacy with standard of care drug

  7. HCC cell lines HepG2-luc Adherent, epithelial-like cells derived from differentiated HCC HepG2-luc2 (CaliperLS) is a luciferase expressing cell line derived from HepG2 Fully permissive for HSV1716 HuH-7 Epithelial-like tumorigenic cells from well-differentiated, hepatocyte-derived carcinoma male Fully permissive for HSV1716

  8. HepG2-luc xenografts * cure = complete and permanent loss of light signal from HepG2-luc xenograft

  9. Growth of HuH-7 xenografts after 2x intravenous injectionof HSV1716 HuH7 xenograft growth until all no virus controls were sacrificed • HSV1716 administered by IV on days 1 and 4 • HuH7 tumours treated with HSV1716 at both doses have greatly reduced growth compared to untreated controls • The difference in growth for untreated vs treated is highly significant by ANOVA (p<0.0001)

  10. 110 no virus 100 1e7 90 80 1e6 70 Percent survival 60 50 40 30 20 10 0 0 10 20 30 40 50 day Survival of mice with HuH7 xenografts after 2x IV injection of HSV1716 • HSV1716 administered by IV on days 1 and 4 • Enhanced survival in both groups treated with HSV1716 (p = 0.0008)

  11. HuH-7 xenografts : Lower dose virus – spreading out the virus doses. • HSV1716 administered by IV on days 1 and 14 and 29 • HuH7 tumours treated with HSV1716 at both doses have greatly reduced growth • compared to untreated controls • The difference in growth for untreated vs treated is highly significant by • ANOVA (p<0.0001)

  12. HuH-7 – Survival at lower treatment dose with more spread out virus treatment • HSV1716 administered by IV on days 1 and 14 and 29 • Enhanced survival in both groups treated with HSV1716 (p= 0.0157) • On day 66 when the experiment was stopped:- • 2/6 mice treated with 1x105 pfu were cured • 4/6 mice treated with 1x106 pfu were cured

  13. HSV1716 localisation to HuH7 xenografts • Mice (n=2) were injected IV with increasing amounts of virus. • Tumours were harvested at 72hr and analyses by titration. • Virus only detected in tumours at titre > input at all doses

  14. HSV1716 in pre-clinical HCC: Conclusions 72 hrs after systemic delivery the virus homes in exclusively on the tumour. Tumour growth is significantly reduced in the Huh7 model and survival lengthened. Giving virus treatment for a prolonged period results in a significant porportion of cures in the Huh7 model, even at lower doses of HSV1716. HSV1716 completely eliminated luc expressing HepG2 xenografts in 23 of 25 mice. HSV1716 may synergise with existing HCC treatments (doxorubicin). Results strongly supportive of progression to clinical studies of HSV1716 in HCC.

  15. Acknowledgements Virttu Biologics Dr Joe Conner & Kirsty Learmonth Glasgow University Dept of Infection and Immunity Prof Shelia Graham Collaborate with us!

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