Abstract A048: Enhancing the immune response in locally advanced pancreatic cancer (LAPC) with intratumoral endoscopic ultrasound-guided fine needle injection of large surface area microparticle paclitaxel (LSAM-PTX)
Authors: Hendifar Andrew E. , Wattenberg Max M. , Maulhardt Holly A. , Marin Alyson M. , Wendt Alison E. , Verco Shelagh J. , diZerega Gere S. 
Published: January 2024

Abstract
Background: The complex tumor microenvironment (TME) of locally advanced pancreatic cancer (LAPC) is resistant to immune effector cell infiltration and drug bioavailability, limiting the effectiveness of current systemic therapies. Large Surface Area Microparticle Paclitaxel (LSAM-PTX) was developed for intratumoral (IT) injection to solid tumors to provide a paclitaxel depot at therapeutic levels with a prolonged residence time. We previously reported enhanced tumor kill in LAPC subjects receiving two monthly IT LSAM-PTX injections and demonstrated immunomodulation in the TME. Multiplex immunofluorescence (mIF) performed on pre-treatment biopsy tissue and post-LSAM-PTX resection showed increases in densities of effector T cells and NK cells and decreases in myeloid derived suppressor cells (MDSC). To further evaluate immunomodulation following IT LSAM-PTX therapy, blood samples were obtained for immunophenotyping using flow cytometry (NCT03077685). Methods: Pretreatment samples were obtained from subjects administered four injections (n=14) and at visits throughout the treatment period and up to six months post first LSAM-PTX injection. Flow cytometric analysis was performed using three panels to evaluate absolute counts and percentages of up to 45 immunophenotypes. Results: Treatment with four IT injections of LSAM-PTX (ongoing median overall survival = 12.6 months; follow-up = 12.2 months) was associated with increases in peripheral lymphocytes during the treatment period. An enhancement of immune subsets associated with anti-tumor effector functions was found, including significant increases in circulating CD3+ and CD4+ cells (p=0.0012 and 0.002 respectively) which is consistent with the 4-fold increase in CD4+helper T cells detected in the TME of resected tissue. A significant increase in LAG3+CD8+ T cells was seen following treatment initiation (p=0.048) marking early T cell activation. Increases in circulating CD8+ T cells, B cells, and NK cells were seen during the treatment period corresponding with effector T cells and NK cells increases (4.8-fold increase in density) within the TME. Six months following treatment initiation there was a significant decrease in circulating Treg cells (p=0.0183) and a decrease in peripheral immunosuppressive G-MDSC, consistent with the reduction in MDSC measured in the TME. Notably, systemic taxane toxicities, including immunosuppression, were not reported following IT LSAM-PTX and negligible amounts of paclitaxel were found in blood samples. Conclusion: Immunophenotyping of blood from LAPC subjects treated with IT LSAM-PTX demonstrates immunomodulation to a phenotype associated with anti-tumor immune effects, including favorable immunosurveillance, and is consistent with changes found in the TME in resected tissues. Immunosuppressive cell types typically associated with poor outcomes were reduced at six months. Anti-tumor immunomodulation without immunosuppression suggests that IT LSAM-PTX may be amenable to combination with immunotherapy.
Citation Format: Andrew E. Hendifar, Max M. Wattenberg, Holly A. Maulhardt, Alyson M. Marin, Alison E. Wendt, Shelagh J. Verco, Gere S. diZerega. Enhancing the immune response in locally advanced pancreatic cancer (LAPC) with intratumoral endoscopic ultrasound-guided fine needle injection of large surface area microparticle paclitaxel (LSAM-PTX) [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 A048.