O-P04 Sonodynamic Therapy Complements PD-L1 Immune Checkpoint Inhibition in a Murine Model of Pancreatic Cancer
British Journal of Surgery(2021)
摘要
Abstract Background The emergence of immune checkpoint inhibitors (ICI’s) in the past decade has proven transformative in the area of immuno-oncology. The PD-1 / PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many “immune cold” tumours remain unresponsive to ICI’s. Sonodynamic therapy (SDT) is a targeted anti-cancer treatment that uses ultrasound to activate a sensitiser with the resulting generation of reactive oxygen species (ROS) causing direct cell death. SDT has also been shown to stimulate the adaptive immune system in a pre-clinical cancer model. We investigate the ability of combining ICI and microbubble mediated SDT at controlling tumour growth in a bilateral pancreatic cancer model. Methods Preparation of O2MB-RB are shown below (scheme 1). Cytotoxicity of SDT and immunotherapy in-vivo are illustrated below (Figure 1). Figure 1 highlights that T110299 cells were subcutaneously implanted in the right and left dorsum of C57 mice. Group 1 received an IP injection of anti-mouse PD-L1 antibody (10mg/kg). After 2 hours, mice in this group received an IV injection of O2MB-RB suspension while receiving ultrasound applied to the right-hand-side (target) tumour. Group 2 received the same as Group 1 but no anti PD-L1 antibody; Group 3 received anti-PD-L1 antibody alone and Group 4 remained untreated. Flow cytometry analysis were carried out to investigate tumour infiltrating CD4+ and CD8+ T-lymphocytes. Results The results demonstrated a significant 287% decrease in tumour volume when compared to untreated animals 11 days following the initial treatment with SDT, which reduced further to 369% when SDT was combined with anti-PD-L1 ICI treatment. Analysis of residual tumour tissues remaining after treatment revealed increased levels of infiltrating CD4+ and CD8+ T-lymphocytes (respectively 4.65 and 3.16-fold more) in the off-target tumours of animals where the target tumour was treated with SDT and anti-PD-L1, when compared to untreated tumours. These results suggest that SDT treatment elicits an adaptive immune response that is potentiated by the anti-PD-L1 ICI in this particular model of pancreatic cancer. Conclusions In conclusion, microbubble mediated SDT treatment of a target tumour in a bilateral tumour model of pancreatic cancer, enables growth control at both the target and off-target tumours which is further enhanced when combined with anti-PD-L1 ICI treatment. Combining SDT with anti-PD-L1 ICI treatment, which is also well tolerated, could provide an attractive treatment option for pancreatic cancer, particularly for patients with advanced disease who may not be physically capable of undertaking a toxic chemotherapy regimen.
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