Immune mediated and direct killing of colorectal cancer by reovirus

Colorectal cancer remains the second most prevalent cancer in the world. Novel treatment strategies are necessary, especially for the treatment of metastatic disease. Reovirus is a naturally occurring oncolytic virus which acts by both direct and immune-mediated mechanisms. Having shown promise in early clinical trials, its therapeutic potential may be limited by inactivation following systemic delivery. This study addressed whether reovirus can be shielded from neutralising antibodies by cell carriage, and whether virus-loaded blood or hepatic innate immune effector cells are activated to kill colorectal cancer cells metastatic to the liver in human systems. Reovirus induced oncolysis of SW480, SW620, LoVo and LS174T tumour cells and the mode of cell death was apoptosis. Direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum. Reovirus was protected from neutralisation when loaded onto peripheral blood mononuclear cells and could be handed off to tumour targets for direct oncolytic killing. Moreover, NK cells within reovirus-loaded patient blood mononuclear cells were stimulated to kill tumor targets but not normal hepatocytes; similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. This blood cell carriage has the potential to instigate both direct and innate immune-mediated therapy against human colorectal cancer which has metastasised to the liver.