The effect of pembrolizumab on the healing of colonic anastomosis: a pre-clinical study in Wistar rats

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Background: Pembrolizumab is a monoclonal antibody that targets the programmed cell death-1 (PD-1) protein. Blocking this pathway alters T-cell activity, and has been approved for the treatment of several malignancies, including microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) colorectal cancers. The aim of this study was to evaluate the effect of pembrolizumab on colonic anastomotic healing in a rat model. Methods: Sixty male Wistar rats were randomly divided into 2 groups of 30: a control group, and an experimental group receiving pembrolizumab. Each group was further divided into 3 subgroups of 10 rats, sacrificed on postoperative day (POD) 3, 7 or 14. All animals underwent laparotomy, a 1-centimeter segmental colectomy, and an end-to-end colonic anastomosis. Postmortem evaluation included measuring anastomotic bursting pressure, tissue hydroxyproline levels, and histopathological assessment. Results: Statistically significant differences in bursting pressure (P=0.019) and rupture site (P=0.033) were observed between the groups on POD 7. Tissue hydroxyproline levels were significantly lower in the pembrolizumab-treated subgroups on POD 7 (P=0.003), and POD 14 (P=0.001). Histopathological analysis demonstrated significant differences on POD 3, in neovascularization (P=0.026), fibroblast ingrowth (P=0.005), and collagen deposition (P=0.030), suggesting impaired inflammatory-phase healing. Conclusions: This experimental study suggests that a high single dose of pembrolizumab may negatively affect colonic anastomotic healing in rats. Further studies are necessary to determine the safety of intestinal anastomosis in both emergency and elective clinical settings.

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