37P Synthetic tumour-infiltrating interleukin (IL)-12 for targeted and tolerable immunotherapy reduces metastasis in pancreatic cancer

Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) is a root cause of lethality in patients. The metastasis promoted by abundant proteases the PDAC microenvironment. Synthetic immuno-oncology opens new avenues towards overcoming limitations standard immunotherapy agents, previously unsuccessful PDAC. Anti-tumour cytokines such as IL-12 poorly infiltrate stroma solid tumours and trigger toxicity. Here, exploiting PDACs, targeted tolerable masked Collagen-Binding Domain CBD-Il12 (mCBD-Il12) was produced fusing mask to p35 subunit Il-12 through cleavable linker. This linker cleaved PDAC-specific proteases, leading activation mCBD-Il12 upon tumour infiltration. Human samples were analysed for expression MMP2/9 PLAU established subtypes (classical quasi-mesenchymal). mCBD-IL12 with sensitive protease activity therefore HEK293F cells purified using immobilised metal affinity size exclusion chromatography. ability various murine tissues their associated cleave verified western blotting. Finally, molecule tested metastatic mesenchymal pancreatic syngeneic mouse model. quasi-mesenchymal subtype found express MMP2/9/PLAU higher degree than other Collisson/Sadanandam subtypes. In addition, we be readily lysate contrast non-cancerous tissue vitro. Interestingly, considerably reduce number liver metastases ascites volume compared wild-type or controls colour varied from white light red mCBD-Il12, dark controls. Analysis blood-based pending. MCBD-Il12 novel bioengineered that seems suppress models. Further studies are required investigate changes microenvironment immune infiltrates involved.