@article{358ca45636714e31abf6acfcf7afd668,
title = "Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy",
abstract = "Background & Aims: The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. Methods: A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. Results: The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti–PD-1 antibody. HA degradation in combination with FAKi and anti–PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti–PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid–derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)–expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti–PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. Conclusions: This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.",
keywords = "Anti–PD-1 Antibody, CXCR4, FAK, Hyaluronan, Pancreatic Ductal Adenocarcinoma",
author = "Blair, {Alex B.} and Jianxin Wang and John Davelaar and Andrew Baker and Keyu Li and Nan Niu and Junke Wang and Yingkuan Shao and Vanessa Funes and Pan Li and Pachter, {Jonathan A.} and Maneval, {Daniel C.} and Felipe Dezem and Jasmine Plummer and Chan, {Keith Syson} and Jun Gong and Hendifar, {Andrew E.} and Pandol, {Stephen J.} and Richard Burkhart and Yuqing Zhang and Lei Zheng and Arsen Osipov",
note = "Funding Information: Funding This work was supported in part by a research grant from Halozyme , independent from Verastem Oncology and Bristol-Meyers Squibb, and a National Institutes of Health ( NIH ) National Cancer Institute ( NCI ) P01 grant P01CA247886. VS-4718 was provided by Verastem Oncology, PEGPH20 was provided by Halozyme, and anti-CXCR4 antibody was provided by Bristol-Meyers Squibb via the International Immune Oncology Network (II-ON) program, all independently. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Verastem Oncology, Halozyme, or Bristol-Meyers Squibb. Alex Blair is supported by NIH NCI grant T32 CA126607 . Arsen Osipov is supported by NIH NCI grant K08 CA259456 and a Conquer Cancer Foundation ASCO Career Development Award. Lei Zheng is supported by NIH NCI grants R01 CA169702, R01 CA197296, P01 CA247886, Specialized Programs of Research Excellence ( SPORE ) grant P50 CA062924 , and grant P30 CA006973 . Funding Information: Conflicts of interest These authors disclose the following: Lei Zheng receives grant support from Bristol-Meyers Squibb, Merck, AstraZeneca, iTeos, Amgen, NovaRock, Inxmed, and Halozyme, is a paid consultant/advisory board member at Biosion, Alphamab, NovaRock, Xilio, QED, Natera, Novagenesis, Ambrx, Snow Lake Capitals, Amberstone, and Mingruizhiyao, and holds shares at Alphamab and Mingruizhiyao. Jonathan A. Pachter is employed by Verastem Oncology. Daniel C. Maneval is employed by Halozyme. The remaining authors disclose no conflicts.Funding This work was supported in part by a research grant from Halozyme, independent from Verastem Oncology and Bristol-Meyers Squibb, and a National Institutes of Health (NIH) National Cancer Institute (NCI) P01 grant P01CA247886. VS-4718 was provided by Verastem Oncology, PEGPH20 was provided by Halozyme, and anti-CXCR4 antibody was provided by Bristol-Meyers Squibb via the International Immune Oncology Network (II-ON) program, all independently. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Verastem Oncology, Halozyme, or Bristol-Meyers Squibb. Alex Blair is supported by NIH NCI grant T32 CA126607. Arsen Osipov is supported by NIH NCI grant K08 CA259456 and a Conquer Cancer Foundation ASCO Career Development Award. Lei Zheng is supported by NIH NCI grants R01 CA169702, R01 CA197296, P01 CA247886, Specialized Programs of Research Excellence (SPORE) grant P50 CA062924, and grant P30 CA006973. Publisher Copyright: {\textcopyright} 2022 AGA Institute",
year = "2022",
month = nov,
doi = "10.1053/j.gastro.2022.06.027",
language = "English (US)",
volume = "163",
pages = "1267--1280.e7",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "5",
}