Abstract B004: EUS guided local administration of large surface area microparticle paclitaxel with neoadjuvant chemotherapy in locally advanced pancreatic cancer: A single center experience
Authors: Gopakumar Harishankar , Khan Aqsa , Zelt Christina M. , Rumple Ashley , de Leon Mariajose Rojas , Sharma Neil R. 
Published: January 2024

Background: Locally advanced pancreatic cancer (LAPC) is defined as an unresectable tumor due to extensive vascular involvement without evidence of metastatic spread. Neoadjuvant chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-nab-paclitaxel (gem-nab) are the preferred treatments in LAPC. These treatments downstage LAPC to resectable disease in about 10%–35% of patients resulting in an increase in median survival. However, intravenous paclitaxel's hydrophobic, protein-bound nature, short half-life, and intermittent dosing hamper tumor tissue exposure time, resulting in suboptimal intratumoral bioavailability that may facilitate tumor resistance. Limited downstaging to R0 resection is likely due, in part, to the desmoplastic, fibrotic tumor microenvironment in LAPC and poorly vascularized stroma reducing availability of IV drug to tumor cells. To address this, large surface area microparticle paclitaxel (LSAM-PTX) was developed (NanOlogy LLC) for intratumoral (IT) delivery with a mean particle size (DV50) of about 2.5 µm and 3-fold increase in specific surface area over unprocessed drug. The relatively large particle size facilitates tumor retention, and increased surface area allows continuous drug release in tumor over an extended time, along with negligible systemic exposure. Methods: Data were collected prospectively on 6 of 13 (46%) subjects with LAPC who received EUS-guided fine needle injection (EUS-FNI) of LSAM-PTX in addition to neoadjuvant chemotherapy and subsequently underwent surgery at our institution from 2018 to 2019 (NCT03077685). Each subject underwent two EUS-FNI procedures four weeks apart to deliver IT LSAM-PTX suspension (15 mg/mL) in a volume equivalent to 20% of the tumor volume up to 5 mL of drug. Histopathological and immunophenotypic profiling using multiplex immunofluorescence (mIF) was performed on tumor site tissue from pre-LSAM-PTX biopsies and the resected tumor. Results: The mean duration from EUS-FNI to surgery was 6.91 months (range: 3.68-12.22 months). Histopathology was evaluated from the resected specimens to assess treatment response. Five of six subjects (83%) had R0 resections. Of the five R0 resections, one subject had a pathologic complete response, one had 10% and two had 10-20% viable tumor, and one had a partial response with tumor regression. Focal necrosis was also reported in the lone subject with an R1 resection. Immunophenotypic profiling of tissue showed an increase in adaptive and innate immune cell density, an increase in NK cells in the tumor microenvironment, and a decrease in the myeloid/MDSC populations. Conclusions: EUS-FNI of LSAM-PTX, added to neoadjuvant chemotherapy, was safe and resulted in a significant reduction in tumor volume, along with significant tumor necrosis, and favorable changes in tumor immunophenotypic configuration. These preliminary results suggest that adding LSAM-PTX to neoadjuvant chemotherapy could increase the rate of downstaging of LAPC to resectable disease and improve clinical outcomes.

Citation Format: Harishankar Gopakumar, Aqsa Khan, Christina M. Zelt, Ashley Rumple, Mariajose Rojas de Leon, Neil R. Sharma. EUS guided local administration of large surface area microparticle paclitaxel with neoadjuvant chemotherapy in locally advanced pancreatic cancer: A single center experience [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B004.