Coxsackievirus A21 used as an oncolytic immunotherapy for cancer

Abstract

Oncolytic viruses selectively target and kill cancer cells by direct lysis and by stimulating a tumour antigen specific immune response. These promising therapeutic agents target multiple cancers and one such agent, T-Vec (Talimogene laherparepvec) has been licensed for treatment of malignant melanoma. We investigated the potential of Coxsackievirus A21 (CVA21) as a treatment for bladder and pancreatic cancers. The human bladder cancer cell-lines were tested and cytolytic ability of CVA21 depended on the expression of the intercellular adhesion molecule -1 (ICAM-1) viral entry receptor which was increased by Mitomycin C, this led to enhanced viral replication and cell death. CVA21 oncolysis induced immunogenic apoptosis as characterised by an increase in expression of ICD markers and apoptosis markers. In addition, MB49/ICAM-1 bladder cancer cells undergoing CVA21-induced ICD led to MB49 tumour rejection in a syngeneic murine bladder cancer model, protection was provided by CD4+ T cells. We evaluated the mechanism of resistance to CVA21 infection in human pancreatic cancer cell-lines. Despite the presence of high ICAM-1, BxPC-3 cell-line was resistant to CVA21 oncolysis and no viral protein was detected. As no genetic mutation was detected in the ICAM-1, an investigation of the mutational background revealed a lack of KRAS mutations in the BxPC-3 cell-line. This lack of KRAS mutation has previously shown to be involved in resistance to virus susceptibility. The therapeutic potential of CVA21 was evaluated by a murine bladder cancer model. Although, CVA21 intratumoural administration delayed tumour growth for a short time. There were limitations such as unrestricted tumour growth and short life-span of the model due to which the evaluation of virus induced immune targets for potential combinational approaches was not possible. Although, CVA21 has shown its benefit as monotherapy both in cell-lines and in in vivo model systems emerging data shows enhanced treatment efficacy using oncolytic viruses in combination with other immune modulatory agents.