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Pre-clinical Studies

Cancer indication Comments Pre-clinical activity of CAVATAK™
Corresponding
Clinical Trial
Melanoma CAVATAKTM is being tested in combination with the latest therapies for malignant melanoma, namely immune checkpoint inhibitors including antibodies that block the molecules “programmed death-1” (PD-1) or “cytotoxic T-lymphocyte-associated protein 4” (CTLA-4). These new immunotherapy agents can limit the suppressive effects of cancer cells on the immune system, thereby allowing the patient’s own immune system to target the tumour. The use of CAVATAKTM as a “tumour-immunoagitator” in combination with immune checkpoint inhibitor antibodies is showing promise in preclinical murine models of melanoma, and forms the basis for the Phase 1b MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) human trial to commence in 2015. 2014 Oral Presentation at the Eight International Conference on Oncolytic Virus Therapeutics (Oxford, UK).2014 September ESMO (European Society for Medical Oncology, Madrid) – Combination of a novel oncolytic immunotherapeutic agent, Coxsackievirus A21 and PD-1 or CTLA-4 blockade.2014  November SITC (The Society for Immunotherapy of Cancer Annual Meeting, Washington)- Combination of a novel oncolytic immunotherapeutic agent, Coxsackievirus A21 and PD-1 or CTLA-4 blockade significantly reduces tumour growth in an immune competent mouse melanoma model

STORM

MITCI

Bladder cancer This work is being conducted by Viralytics Ltd in conjunction with Dr Pandha and Dr Guy Simpson at the University of Surrey (UK).
Combining CVA21 with either radiotherapy or chemotherapy synergistically enhances cytotoxicity in bladder cancer cell lines
2014 Publication at The Eighth International Conference on Oncolytic Virus Therapeutics (Oxford, UK):Major synergy between Coxsackievirus A21 (CAVATAKTM) and radiotherapy or chemotherapy in bladder cancer, due to up-regulation of viral receptors ICAM-1 & DAF.
2013 Publication at The Seventh International Meeting on Replicating Oncolytic Virus Therapeutics (Quebec): Major synergy between Coxsackievirus A21 (CAVATAKTM) and radiotherapy or chemotherapy in bladder cancer cell lines, due to up-regulation viral receptors ICAM-1 & DAF

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CANON

Lung cancer Research into using CAVATAKTM for the treatment of lung cancer is an active R&D project for Viralytics Ltd.
Currently we have several poster publications demonstrating the efficacy of CAVATAKTM for the treatment of non-small cell lung carcinomas in immune deficient mouse models. The use of CAVATAK™ together with immune checkpoint inhibitors (eg. anti-PD-1 and/or anti-CTLA-4)  shows significant activity in immunecompetent models of lung cancer.
2016 Poster at the American Association for Cancer Research (Annual meeting, New Orleans, USA): Elevated immune activity following an anti cancer combination therapy of a novel oncolytic immunotherapy agent, CAVATAK (Coxsackievirus A21), and immune checkpoint blockade
2014 Publication at The Eighth International Conference on Oncolytic Virus Therapeutics (Oxford, UK):Synergistic Activity of Coxsackievirus A21 (CVA21) and Docetaxel in Non-Small Cell Lung Cancer (NSCLC)
2013 Publication at The Seventh International Meeting on Replicating Oncolytic Virus Therapeutics (Quebec):Investigation of Potential Oncolytic Effects of Replication-Competent Coxsackievirus A21 (CVA21) in Combination with Chemotherapy on Various Lung Carcinomas
2011 Australasian Virology Society Meeting (Kingscliff NSW): Establishment of an Orthotopic Murine Lung Cancer Model For The Testing of Coxsackievirus A21 (CVA21) Virotherapy
2011- 14th World Conference on Lung cancer: Oncolytic Activity of Coxsackievirus A21 (CAVATAKTM) in Human Lung Cancer

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Prostate cancer The pre-clinical activity of CAVATAKTM in prostate cancer was previously published in 2008. This work found that both CAVATAKTM (CVA21) and EVATAKTM (Echovirus 1) had anti-cancer activity against prostate cancer cell lines in vitro and in vivo. Berry, L. J., Au, G. G. G., Barry, R. D., & Shafren, D. R. (2008). Potent oncolytic activity of human enteroviruses against human prostate cancer. The Prostate, 68(6), 577–587. doi:10.1002/pros.20741

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Phase I – PSX-X04 (completed)

Breast cancer Pre-clinical indicates that CAVATAKTM is highly effective against breast cancer xenografts in immunodeficient mice. Further work in 2010 showed that CAVATAKTM oncolysis was enhanced when used in combination with doxorubicin hydrochloride (a chemotherapeutic agent commonly used for the treatment of breast cancer). Skelding, K. A., Barry, R. D., & Shafren, D. R. (2010). Enhanced oncolysis mediated by Coxsackievirus A21 in combination with doxorubicin hydrochloride. Investigational New Drugs.Skelding, K. A., Barry, R. D., & Shafren, D. R. (2009). Systemic targeting of metastatic human breast tumor xenografts by Coxsackievirus A21. Breast Cancer Research and Treatment, 113(1), 21–30.

Phase I – PSX-X04 (completed)

Multiple myeloma CAVATAKTM effectively targeted cancerous multiple myeloma cells from patient biopsy material while leaving normal peripheral blood mononuclear cells intact.
This is an ongoing area of research for Viralytics Ltd.
Au, G. G. G., Lincz, L. F., Enno, A., & Shafren, D. R. (2007). Oncolytic Coxsackievirus A21 as a novel therapy for multiple myeloma. British journal of haematology, 137(2), 133–141.

Not yet in clinical trials

Pancreatic cancer Pancreatic tissue biopsies show high levels of ICAM-1 expression in pancreatic cancer cells vs normal cells. This data supports the notion that CAVATAKTM may also be highly efficacious in the selective destruction of pancreatic cancer cells compared to non-cancerous cells. In a pilot study of PANC-1 tumour cells in SCID Balb/C mice, tumours responded to both intratumoural and intravenous delivery of CAVATAKTM compared to the saline control. Presentation at 10th International Oncolytic Virus Conference, Vancouver, Canada – October 2016: Pre-clinical Investigation of CAVATAK (Coxsackievirus A21) as a Potential Treatment for Pancreatic Cancer.

Au, G. G., Davies, B., Chan, E. S., Green, E., Stewart, J., & Shafren, D. R. (2011, March 16). Oncolytic activity of Coxsackievirus A21 (CAVATAKTM) in human pancreatic cancer The 6th International Conference on Oncolytic Viruses As Cancer Therapeutics. Las Vegas.

Not yet in clinical trials

Malignant Glioma Immunohistochemical staining of glioblastoma multiforme specimens were all strongly positive for ICAM-1. Of the 5 normal brain specimens examined for ICAM-1 expression, all were negative and did not stain for ICAM-1. The majority of glioma cell lines tested were sensitive to CAVATAKTM treatment.
In orthotopic mouse models of brain cancer, some evidence of tumour shrinkage and a delay in tumour growth was seen at early time points, however long lasting tumour regression was not observed in these athymic nude mouse models. Levels of neutralizing antibodies were detected in mouse serum.
Chan, E. S., G, A. G., Guha, A., & Shafren, D. R. (2010, September 11).Coxsackievirus A21 as an oncolytic virotherapy agent against malignant glioma POSTER EUROPIC 2010: XVI Meeting. St Andrews.Chan, E., Quah, M. Y., Wong, Y. V. Y., Shafren, D. R., & Au, G. G. (2011, December 2). The Oncolytic Activity of Low Pathogenic Human Enteroviruses in Combination with Carboplatin for the Treatment of Malignant Glioma Australasian Virology Society Meeting 2011. Kingscliff.Au, G. G., Haley, E. S., O’Neil, E., Barry, R. D., Guha, A., & Shafren, D. R. (2008, September 11). Coxsackievirus A21 oncolytic virotherapy as a novel treatment for malignant glioma POSTER. Hunter Medical Research Institute Conference on Translational Cancer Research.

Not yet in clinical trials

Acute myeloid leukemia (AML) and Chronic lymphocytic leukemia (CLL) This work is carried out in collaboration with Prof Alan Melcher from Cancer Research UK (University of Leeds). AML cell lines expressed only low levels of ICAM-1 and DAF and were not sensitive to CAVATAKTM infection. By contrast, CLL lines did express ICAM-1 and DAF and were directly killed by the virus. Hall, K., Ilett, E. J., Errington, F., Scott, K., Shafren, D. R., Donnelly, O., & Melcher, A. (2013, May 10). Coxsackievirus A21 (CVA21) Immune Cell Interactions and Oncolytic Activity in Leukaemia The 7th International Meeting on Replicating Oncolytic Virus Therapeutics. Quebec City, Quebec, Canada.

Not yet in clinical trials

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