Coldvirus against melanoma

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Clinical Cancer Research Vol. 10, 53-60,

© 2004 American Association for Cancer Research

 

Systemic Therapy of Malignant Human Melanoma Tumors by a Common

Cold-Producing Enterovirus, Coxsackievirus A21

Darren R. Shafren12, Gough G. Au1, Tam Nguyen3, Nicole G. Newcombe1, Erin S.

Haley2, Leone Beagley2, E. Susanne Johansson1, Peter Hersey3 and Richard D.

Barry12

1The Picornaviral Research Unit, Biomedical Science, Faculty of Health, The

University of Newcastle, Newcastle, New South Wales, Australia;2 ViroTarg

Pty. Ltd., Industry Development Centre, Newcastle, New South Wales,

Australia; and3 Immunology and Oncology Unit, Mater Hospital, Newcastle, New

South Wales, Australia

 

ABSTRACT

 

Purpose: The incidence of malignant melanoma continues to increase

worldwide; however, treatment of metastatic melanoma remains unsatisfactory,

and there is an urgent need for development of effective targeted

therapeutics. A potential biological target on the surface of malignant

melanoma cells is the up-regulated expression of intercellular adhesion

molecule (ICAM)-1 and decay-accelerating factor (DAF), relative to

surrounding benign tissue. Coxsackievirus A21 (a common cold virus) targets

and destroys susceptible cells via specific viral capsid interactions with

surface-expressed virus receptors comprising ICAM-1 and DAF.

 

Experimental Design: The oncolytic capacity of a genetically unmodified

wild-type common cold-producing human enterovirus (Coxsackievirus A21,

CAV21) was assessed against in vitro cultures and in vivo xenografts of

malignant human melanoma cells.

 

Results: In vitro studies established that human melanoma cells endogenously

express elevated levels of ICAM-1/DAF and were highly susceptible to rapid

viral oncolysis by CAV21 infection, whereas ICAM-1/DAF-expressing peripheral

blood lymphocytes were refractile to infection. In vivo studies revealed

that the tumor burden of nonobese diabetic severe combined immunodeficient

mice bearing multiple s.c. melanoma xenografts was rapidly reduced by

oncolysis mediated by a single administration of CAV21. The antitumor

activity of CAV21 was characterized by highly efficient systemic spread of

progeny CAV21, with oncolysis of tumors also occurring at sites distant to

the primary site of viral administration.

 

Conclusions: Overall, the findings presented herein demonstrate an important

proof of principle using administration of replication-competent CAV21 as a

potential biological oncolytic agent in the control of human metastatic

melanoma.

 

Het krantenartikel:

 

 

The common cold virus most people try their hardest to avoid is very likely

to be the cure for malignant melanoma, Australian scientists have discovered

in a major breakthrough announced. A team of researchers at the University

of Newcastle believe they have made an exciting discovery in the treatment

of the usually deadly skin cancer of which Australia with its fair-skinned

people and hot sun has the highest rate in the world. " We have established

that melanoma cells can be destroyed by infecting them with a common cold

virus, " the lead researcher, associate professor Darren Shafren said. " We

believe this is a significant break-through in the development of the

treatment of melanoma. We are very excited about it. " " The results we have

had using human cells and also in animal studies have been very exciting. If

we can replicate this success in human trials then it could be available

within a year or two. " The research has just been published as the cover

story in the January 2004 edition of Clinical Cancer Research, the journal

of the American Association for Cancer Research (AACR). Shafron, 40,

believes a treatment of the disease will be tested first on a few terminal

patients and could be available even for advanced cases almost immediately.

But it would be subject to regulatory hurdles, which could take longer. " I

would say it should be available within one to two years, but it could be a

lot earlier than that if we get lucky, " Shafron told AFP in an interview.

" We are pretty optimistic about it as long as we can get through the red

tape. I can't really say too much about it, but we have stuff ready to go

and we just have to do the best we can to get through the regulatory

authorities. " Skin cancer is so common here that it would be of huge benefit

in a country in which one in every two people will develop some form of the

disease at some stage. Some 300,000 Australians will visit a doctor this

year to have a skin cancer removed. Almost 9000 new cases of melanoma are

diagnosed each year, about 1000 Australians die of melanoma, which is the

fifth most common form of cancer. The projected process involves injecting

the common cold virus, the coxsackievirus, into the melanoma site, the virus

replicates itself and is expected then to start to kill off the melanoma.

Shafron says that within weeks, there is a reduction in the size of the

melanoma and it eventually disappears. " When the secondary action begins, we

expect the virus to circulate the body finding and killing off melanomas in

the same manner with the effect that it will seek out and kill melanomas

that may be undetectable, " he added. " This is a community occurring virus,

not a manufactured drug or a genetically altered virus. We believe it could

even be effective for people with advanced melanoma. " The work, based on

technology developed by the picornavirus department at the university over

the past four years, is being conducted at the local biotechnology company

ViroTarg's laboratory in the Royal Newcastle Hospital 150 kilometres north

of Sydney. AFP