The combination of Reolysin and belinostat results in significantly enhanced antilymphoma activity and reovirus replication in parental and belinostat-resistant Karpas-299 tumors. (A) Reolysin enhances the antilymphoma activity of belinostat in vivo in both Karpas-299 parental (left) and belinostat-resistant tumors (right). Karpas-299 parental and belinostat-resistant tumors were established in NOD-SCID mice. Mice were treated with 5.0 × 10⁶ TCID50 Reolysin once per week intratumorally, 50 mg/kg belinostat once per day intraperitoneally, or the combination of both agents. Tumor volume was measured twice per week. Data are shown as mean ± SEM (n = 10). *P < .05 indicates a significant difference compared with vehicle control or **P < .05 compared with either belinostat or Reolysin single agent treatment. (B) The combination of Reolysin and belinostat is well tolerated in mice. Parental and belinostat-resistant Karpas-299 tumors were established in immunodeficient NOD-SCID mice. Mice were then treated with 5.0 × 10⁶ TCID50 Reolysin, 50 mg/kg belinostat, and the combination. Mouse body weight was measured twice per week. Data are shown as mean ± SD (n = 10). No significant animal weight loss was observed in any of the groups. (C) Reovirus accumulation is significantly greater in belinostat-resistant tumors and when given in combination with belinostat. Tumors were harvested at the end of treatment, and reovirus replication was visualized by electron microscopy. Arrows denote reovirus particles. (D) Quantification of reovirus particles inside parental and belinostat-resistant Karpas-299 tumors. Reovirus accumulation was determined by counting viral particles using ImageJ software. Data are shown as mean ± SD (n = 3). *P < .05 indicates a significant difference from vehicle or belinostat or **P < .05 for treatment with Reolysin monotherapy.