Coxsackievirus A21 as an oncolytic agent for the control of human cancer

Transcription

1 Coxsackievirus A21 as an oncolytic agent for the control of human cancer Dr Gough G. Au PhD Conjoint Research Fellow The University of Newcastle Australia Viralytics Ltd.

2 Viruses can be used to treat cancer

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5 Oncolytic virotherapy Use of viruses to selectively destroy cancer cells while leaving normal cells intact

6 Number of Journal Articles relating to Oncolytic Virotherapy 300 Number of publications Oncolytic Virotherapy Cancer related Monoclonal Antibody therapy

7 In the shadow of Monoclonal Antibody therapies for oncology 3000 Number of publications First FDA approval Rituximab Oncorine Oncolytic Virotherapy Cancer related Monoclonal Antibody therapy Chinese SFDA approval

8 Herpes Simplex Reovirus Virus Measles virus Vesicular Stomatitis Virus Adenovirus Bovine enterovirus Semliki Forest Virus Influenza Recombinant Poliovirus Newcastle Disease Virus Seneca Valley Virus

9 Coxsackievirus A21

10 Coxsackievirus A21 Kuykendall Strain Picornaviridae family Non-enveloped RNA virus Isolated in 1952 Causes the common cold Well characterised VIPERdB: C. M. Shepherd, I. A. Borelli, G. Lander, P. Natarajan, V. Siddavanahalli, C. Bajaj, J. E. Johnson, C. L. Brooks, III, and V. S. Reddy (2006). VIPERdb: a relational database for structural virology. Nucl. Acids Res. 34 (Database Issue): D386-D389

11 Relative size of CVA21 compared to other oncolytic agents Adenovirus Type 5 (minus spikes) ( nm) Reovirus (70-80 nm) CVA21 (28 nm)

12 CVA21 entry receptors ICAM-1 Intercellular adhesion molecule-1 DAF Decay-accelerating factor

13 DAF assists CVA21 to the cell surface ICAM-1 is required for CVA21 infection

14 After viral receptor mediated cell-entry Viral replication begins Viral assembly Release of new viruses! Death of host cell

15 Virus-Cell Entry ICAM-1 DAF

16 Many cancer cells express higher levels of surface ICAM-1 and DAF compared to normal cells

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18 Serendipitous discovery in 1999: CVA21 kills melanoma cells in vitro

19 Cells and tissues that express upregulated ICAM-1 and/or DAF Melanoma Breast cancer Prostate cancer Head and Neck cancer Multiple myeloma Malignant glioma Pancreatic cancer Lung cancer

20 In vitro sensitivity of prostate cancer cell lines Berry, L. et al. (2008) Potent Oncolytic activity of human enteroviruses against human prostate cancer. The Prostate, 68,

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22 PC3 Xenograft model in SCID mice Berry, L. et al. (2008) Potent Oncolytic activity of human enteroviruses against human prostate cancer. The Prostate, 68,

23 Pre-clinical efficacy of CVA21 in luciferase expressing melanoma and breast cancer xenografts i.v. PBS i.v. CVA21 MV-3 (Melanoma) MDA-MB-231 (Breast) ~35 days post treatment

24 Baseline representative immuno-histochemical staining for cell surface ICAM-1 in a paraffin embedded formalin fixed section of human malignant melanoma. Neg Ig-control anti-icam-1

25 ICAM-1 expression on malignant glioma tissues Figure 1: Immunohistochemical staining of ICAM-1 on normal vs. human glioma specimens. ICAM-1 expression was examined on three normal (A) and three glioma (B) formalin fixed specimens. The matching control stained tissue is shown alongside for comparison. All GBM (glioblastoma multiforme) specimens stained strongly for ICAM-1 as shown by the dark brown staining in the right hand column of panel B.

26 Multiple myeloma cells from clinical BM samples express ICAM-1 CD138 is a surface marker for multiple myeloma cells

27 Multiple myeloma cells from clinical BM samples express ICAM ICAM CD138 CD138 is a surface marker for multiple myeloma cells

28 CAVATAK

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30 X01: Open-label, cohort study of 1 dose of CAVATAK given intratumorally in stage IV melanoma subjects: COMPLETED Sponsor: Study medication: Dose: Dosage forms: Route: Study design: Total sample size: Study population Dosing regimen: Primary objective: Secondary objectives: TGA Special access scheme CAVATAK (CVA21) 2 x 10 7 TCID50 CVA21 is presented as a sterile, injectable solution in normal saline. Each vial of solution contains 1.0 ml of CVA21 in the concentration of 1 x 10 7 Intratumoural open-label, cohort 2 patients Patients with stage IV melanoma with at least on metastatic deposit 10-30mm in diameter A single dose of x 10 7 TCID50 To determine safety and tolerability of a single dose of CVA21 1. To determine tumour response of injected and remote tumours 2. To assess primary as well as secondary viremias 3. To determine predictors and correlates of adverse events 4. To determine the time course and frequency of development of anti-cva21 neutralising antibodies

31 X02: A phase I, open-label, cohort study of 1 dose of CAVATAK given intratumourally in stage IV melanoma subjects: COMPLETED Sponsor: Study medication: Dose: Dosage forms: Route: Study design: Total sample size: Study population Dosing regimen: Primary objective: Secondary objectives: Psiron Ltd (Viralytics Ltd) CAVATAK (CVA21) 2 x 10 7 TCID50 CVA21 is presented as a sterile, injectable solution in normal saline. Each vial of solution contains 1.0 ml of CVA21 in the concentration of 1 x 10 7 Intratumoural Phase I, open-label, cohort 3 patients Patients with stage IV melanoma with at least on metastatic deposit 20-50mm in diameter A single dose of 2 x 10 7 TCID50 To determine safety and tolerability of a single dose of CVA21 1. To determine tumour response of injected and remote tumours 2. To assess primary as well as secondary viremias 3. To determine predictors and correlates of adverse events 4. To determine the time course and frequency of development of anti-cva21 neutralising antibodies

32 Conclusions: X01&X02 CAVATAK -melanoma trial There were no serious or severe adverse events during the study and no adverse events considered to be related to the study medication or causing withdrawal from the study. There were no clinically significant haematology, biochemistry or vital signs results, and physical examination results were all normal. All patients developed protective levels of specific serum anti-cva21 antibody at 7-14 days post-injection. CVA21 injection into one subcutaneous lesion in patients with Stage IV metastatic melanoma, appear to be tolerated. CVA21 RNA detected in the injected nodules of 2 patients despite the presence of serum neutralising anti-cva21 antibody.

33 X03: A phase I, open-label, cohort study of 2 doses of CAVATAK given intratumourally in stage IV melanoma subjects: COMPLETED Sponsor: Study medication: Route: Study design: Total sample size: Study population Dosing regimen: Primary objective: Viralytics Ltd CAVATAK (CVA21) Intratumoural Phase I, open-label, cohort 9 (3 patients per cohort) Patients with stage IV melanoma with at least on metastatic deposit 20-50mm in diameter The total dose will be divided into two doses, given 48 hr apart To determine safety and tolerability of three different total doses, divided into two equal doses, of CVA21 injected intratumourally, 48 hr apart

34 Conclusions: X03 CAVATAK -melanoma trial All patients adequately tolerated the multiple single tumour injections up to a final dose of 2 x 10 9 TCID50. There were no serious adverse events deemed to be probably, or highly probably, related to study drug. Five of nine (55.55 %) patients experienced reductions in injected tumour volume or tumour stabilisation following multiple single tumour injections with CAVATAK

35 X04: A phase I, open-label, cohort study of multiple doses of CAVATAK given Intravenously to stage IV solid tumour cancer patients bearing ICAM-1 and/or DAF expressing tumours: IN PROGRESS Sponsor: Study medication: Route: Total sample size: Study population Dosing regimen: Primary objective: Viralytics Ltd CAVATAK (CVA21) Intravenous infusion 26 (2 patients per 13 cohorts) Stage IV breast, melanoma or prostate cancer patients bearing ICAM-1 and/or DAF expressing tumours that have failed or refused conventional anti-cancer treatments Intravenous infusions of a 100 ml bag of normal saline with the prepared dose of CAVATAK administered via an infusion pump The primary objective of the study is to determine the safety and tolerability of CVA21 given by intravenous infusion in multiple escalating doses.

36 X06: A Phase I, Open-label, Dosage Escalation, Study of Multiple Doses of CAVATAK Administered Intratumourally in the Treatment of Squamous Cell Carcinoma of the Head and Neck Bearing ICAM-1 Receptors: IN PROGRESS Sponsor: Study medication: Route: Study design: Total sample size: Study population Dosing regimen: Viralytics Ltd CAVATAK (CVA21) Intratumoural Phase I, open-label, cohort 9 (3 patients per cohort) Treatment of recurrent, unresectable squamous cell carcinoma of the head and neck 1, 3 or 6 doses of CAVATAK (10 9 TCID50) at 48 hour intervals Primary objective: Safety and tolerability of patients to multiple doses of CAVATAK

37 PHASE II PROPOSED: VLA-07:A Study of Intratumoral CAVATAK in Patients With Stage IIIc and Stage IV Malignant Melanoma Sponsor: Study medication: Route: Study design: Total sample size: Viralytics Ltd CAVATAK (CVA21) Intratumoural Phase II: Open Label: Single group assignment 63 patients Study population Dosing regimen: Patients with Stage IIIc and Stage IV Malignant melanoma Each patient will receive 10 intratumoral injections of CAVATAK. Each dose will contain 10 9 TCID50 virus. Primary objective: Safety/Efficacy!Study. Immune-related Disease Control Rate (irdcr) at 6 months Investigational New Drug Application (IND) Lodged November 1, 2010.

38 Overview of CAVATAK development Preclinical Phase I Phase II Phase III Melanoma IT Melanoma, Breast, Prostate IV Head & Neck IT Prostate IT Glioma Lung Pancreatic Multiple myeloma

39 Mr Bryan Dulhunty CEO and Managing Director Professor Darren Shafren CSO and Inventor of the Technology Mr Stephen Goodall Chief Operating Officer!

40 Acknowledgments A/Prof Darren Shafren A/Prof Richard Barry Dr Susanne Johansson Dr Roberta Karpathy Mr Robert Herd Mrs Bronwyn Davies Mrs Rebecca Ingham Mrs Jaclyn Burgess Ms Erin Green Ms Penny Yates Ms Ruth Buxton Students: Mr Eric Chan, Mr Min Yuan Quah and Ms Yvonne Wong Dr Linda Berry