Systemic Therapy of Malignant Human Melanoma Tumors by a Common Cold-Producing Enterovirus, Coxsackievirus A21

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 surfaceexpressed 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.

Entérovirus non poliomyélitiques et pathologies respiratoires

“…Ce modèle murin permettra de mieux appréhender les mécanismes inflammatoires développés chez l'hôte au cours des infections respiratoires basses par les picornavirus humains. Comme les coxsackievirus A utilisent égale-ment les récepteurs ICAM-1 pour entrer dans la cellule cible respiratoire, on pourrait envisager de développer un modèle proche pour des infections respiratoires basses par les entérovirus [43].…”

History of Oncolytic Viruses: Genesis to Genetic Engineering

“…However, because of their pathogenicity, most human viruses cannot be considered suitable as drugs. Possible exceptions include Coxsackie virus A21, an oncolytic human picornavirus whose pathogenicity is limited to mild upper respiratory tract infections, 95 and human reovirus, which is oncolytic in preclinical models but apparently apathogenic in infected humans. 96 Fortunately, most viruses can now be adapted or engineered to eliminate their pathogenicity without destroying their oncolytic potency.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…103 Given that ICAM-1 and DAF are overexpressed in melanoma cells, efforts to evaluate the oncolytic potential of wildtype CVA-21 (and other coxsackieviruses) have mainly focused on this disease. 104 Currently ongoing phase I/II clinical trials employing intratumoral injection of wildtype CVA-21 (CAVATAK) in Australian patients with advanced melanoma are showing promising preliminary results. 105 All (pre) clinical work so far has been conducted with wildtype CVA, while no progress has been made regarding conditional replication, arming or targeting.…”