Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, coxsackievirus a21.
OBJECTIVE
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.


METHODS
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.
Shafren
Darren R
DR
The Picornaviral Research Unit, Biomedical Science, Faculty of Health, The University of Newcastle, Newcastle, New South Wales, Australia.
Au
Gough G
GG
Nguyen
Tam
T
Newcombe
Nicole G
NG
Haley
Erin S
ES
Beagley
Leone
L
Johansson
E Susanne
ES
Hersey
Peter
P
Barry
Richard D
RD
D000818:Animals; D001691:Biological Therapy; D018958:CD55 Antigens / Q000378:metabolism; D029821:Enterovirus A, Human / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012878:Skin Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation
D018958:CD55 Antigens; D018799:Intercellular Adhesion Molecule-1