436. Coxsackievirus A21 Has Potent Oncolytic Activity in Multiple Myeloma

Abstract

The Enterovirus, Coxsackievirus A21 (CVA21) has been shown to have a significant oncolytic effect on melanoma tumors grown in mice (Shafren et al. Clin Cancer Res, 2004). CVA21 binds to decay-accelerating factor (DAF) and requires a second receptor intercellular adhesion molecule 1 (ICAM-1) for entry into cells. We wanted to explore the effect of CVA21 on multiple myeloma cell lines and xenografts. CVA21 was propagated and titered on H1-HeLa cells. FACScan analysis was performed with human multiple myeloma cell lines (KAS6/1, MM1, JJN-3, ARH-77). All the cell lines tested were found to express surface receptors for both DAF and ICAM-1, making them viable candidates for CVA21 infection. We continued with in vitro studies and found cell lines that were incubated with decreasing amounts of CVA21, showed rapid cytopathic effect in doses as low as MOI = 0.0014 for three of the cell lines tested (dose for CPE with JJN-3 was MOI = 0.028). With in vivo studies in SCID mice bearing human myeloma xenografts, tumors quickly and completely responded to CVA21 (both IV and IT administration). However, as promptly as the tumors regressed the mice became sick with hind-limb paralysis and quickly died. Pathology reports showed complete ablation of all tumor tissue but also signs of widespread myositis in muscle tissues. CVA21 virus was recovered from muscle biopsies but there was no evidence of CNS infection. Toxicity was observed in tumor bearing animals with a CVA21 dose as low as 560 TCID50. In an attempt to ameliorate the myositis, adenoviruses coding for mouse IFN-|[alpha]| was administered prior to CVA21 therapy. Blood levels of IFN-|[alpha]| were measured by ELISA and were 1500-3000 pg/ml compared to 150 pg/ml in untreated control mice. However, there was little impact on tumor response or survival. CVA21 is a promising anti-myeloma agent but its associated toxicity in SCID mice is a major concern. Potential solutions to this problem are currently under investigation.