Abstract 1858: Enhanced delivery of anti PD-1 antibody to liver tumors in oncopig using pressure enabled drug delivery (PEDD) versus a systemic delivery
Authors: Jaroch David Benjamin , Ghosh Chandra C. , Guha Prajna , Katz Steven , Cox Bryan F. , Hullinger Thomas G. 
Published: June 2023

Abstract
Background: Anti-PD-1 checkpoint inhibitors have been developed to mitigate immune suppression by reversing T cell exhaustion. Typically, checkpoint inhibitors are delivered systemically, which may be inadequate due to poor drug distribution and limited penetration into solid tumors due to high intra-tumoral pressure. In such tumors, interstitial fluid pressure and solid stress restricts blood flow and therapeutic agent distribution throughout the tumor stroma. Pressure enabled drug deliveryTM (PEDDTM) has been demonstrated to improve therapeutic delivery in pre-clinical models and in patients. PEDD has also been shown to reduce off-target tissue exposure to embolics while increasing intra-tumoral therapeutic concentration. We hypothesized that PEDD hepatic arterial infusion (HAI) using a TriNav device would enhance anti-PD-1 antibody delivery to porcine liver tumors when compared to systemic delivery.
Methods: The study was conducted in transgenic pigs (oncopigs) 35-50kg in weight. Explanted liver tissue was treated to induce oncogene expression and re-implanted in the liver at 4 locations for tumor formation. A fixed dosage (1 mg/animal) of fluorescently labeled InVivoSIM anti-human PD-1 (AB_2894731) checkpoint inhibitor (CPI) was infused in 10ml of PBS at 2 ml/min. The TriNav was positioned within a HA branch supplying a hepatic lobe with a fully formed tumor for local-regional infusion. Systemic infusion was conducted through the femoral vein. Liver tissue was collected 1 hour following infusion and drug levels were quantified by nearIR fluorescence imaging on sequential 1 cm thick sections. NearIR images were overlaid on color images, tumor border delineated, and the mean fluorescent CPI signal was calculated in concentric rings relative to the tumor border.
Results: A significant 2.6-to-5.4-fold increase in CPI signal intensity was observed from 15mm within the tumor to 30mm from the outer edge of tumor with PEDD using the TriNav device when compared to systemic delivery (p ≤ 0.05). PEDD delivery also resulted in significant 2.5-to-3.9-fold enrichment from 5mm within the tumor to 10mm surrounding the tumor (relative to normal tissue within the treated lobe, p ≤ 0.05). No significant difference in signal intensity was observed in peri-tumoral regions and a reduction in signal was observed in tissues 5mm to 15mm within the tumor relative to normal tissue (p ≤ 0.05) following systemic CPI infusion.
Conclusions: This study demonstrates that HAI delivery of CPI into liver tumors in the oncopig via PEDD using a TriNav device resulted in superior delivery compared to systemic infusion. Importantly, PEDD significantly concentrated delivery of CPI into the tumors and within the rapidly growing margin of the tumors where target immune cells such as lymphocytes are present.
Citation Format: David Benjamin Jaroch, Chandra C. Ghosh, Prajna Guha, Steven Katz, Bryan F. Cox, Thomas G. Hullinger. Enhanced delivery of anti PD-1 antibody to liver tumors in oncopig using pressure enabled drug delivery (PEDD) versus a systemic delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1858.