Pancreatic Retrograde Venous Infusion (PRVI) Significantly Enhances Delivery of NearIR Labelled SD-101 TLR9 Agonist to Targeted Regions of the Porcine Pancreas.

Advanced pancreatic ductal adenocarcinoma (PDAC) has an overall 5-year survival rate of only 10%.  Systemically delivered conventional chemotherapy and immunotherapy have had limited success in locally advanced PDAC patients, in part, due to high intratumoral pressure which restricts blood flow and therapeutic absorption. Here we describe a novel trans-venous approach for delivering labeled SD-101 (SD-101^L), a novel immune modulating TLR9 Type C agonist, into pancreatic tissues under elevated pressure.

Materials and Methods: The study was conducted on normal 40-60kg female swine.  A fixed dosage of nearIR labeled SD-101^L was administered to each animal.  The therapeutic was dispersed in either 10ml (n=5) or 20ml (n=5) of solution to evaluate how infusion volume impacts delivery efficiency.  A third cohort was evaluated to determine if allowing the therapeutic to “dwell” within the vessel at stasis for 20min impacted uptake (10ml infusion, 20min dwell, n=5).  Infusion was conducted through a TriSalus Infusion System (TIS-21120-60) at a rate of 2ml/min into a volume drained by a single vein (Target Tissue) for all cohorts. A 35mmHg maximum vascular pressure threshold was established after device deployment prior to infusion. The remainder of the pancreas remained untreated (Non-Target Tissue). Quantification of tissue uptake within the pancreases was performed by nearIR fluorescence imaging on sequential 1cm thick sections of tissue.

Results:

Target tissues displayed 11.5-fold (10ml, 0min dwell, p=0.003), 10.8-fold (10ml, 20min dwell, p=0.001) and 11.2-fold (20ml, 0min, p=0.018) enrichment in fluorescent signal relative to non-target tissues.  Single vessel infusions resulted in a mean treated volume of 4.5±0.6cm³. Infusion volume and dwell time did not significantly impact target tissue fluorescence intensity or treated tissue volume. Vascular pressure was significantly increased relative to normal venous pressure after device deployment (21.6±1.5mmHg vs 30.2±1.0mmHg, p=0.000) and during infusion (21.6±1.5mmHg vs 33.7±1.5mmHg, p=0.000).

Conclusion:

PRVI methodology significantly increased the concentration of SD-101^L within a targeted infusion region of the pancreas.  The observed 10.8 to 11.5-fold enrichment may be attributed to exposing tissues to concentrated therapeutic solution under elevated pressure, promoting convective transport.  PRVI methodology may allow physicians to improve therapeutic delivery to locally advanced PDAC tumors. These data formed the preclinical foundation for the PERIO-03 clinical trial at MD Anderson Cancer Center.