Abstract LB164: A novel glycomimetic compound (GMI-1757) with dual functional antagonism to E-selectin and galectin-3 attenuates fibrosis, facilitates mononuclear cell infiltration and optimizes anti-PD-L1 therapeutic activity in a pancreatic adenocarcinoma model
Authors: Fogler William E. , Smith Theodore A. , Lee Ji-Won , Locatelli-Hoops Silvia , Stewart David , Peterson John , Magnani John L. 
Published: July 2021

The inability to generate robust anti-tumor responses with therapeutics affecting T cell function has been ascribed to multiple parameters such as the tumor fibrotic compartment and the degree/makeup of host infiltrative cells. These parameters are affected through pathways involving the interaction of galectin-3 and E-selectin with cognate ligands. In the current investigations we assessed the impact of a dual E-selectin and galectin-3 glycomimetic antagonist, GMI-1757, in combination with anti-PD-L1 on tumor progression using an orthotopic pancreatic carcinoma model. Eight days following the orthotopic injection of 5x105 luciferase-enabled Pan02 carcinoma cells into the pancreas of female C57BL/6 mice, mice began daily IP treatment for 11 days with control diluent (C) or 50 mg/kg GMI-1757. Beginning on study day 15 C- or GMI-1757-treated mice were given 10 mg/kg anti-PD-L1 or an isotype control antibody (LTF-2). Sixteen mice were allocated into each of 4 groups: group 1 = C + LTF-2; group 2 = GMI-1757 + LTF-2; group 3 = C + anti-PD-L1; and group 4 GMI-1757 + PD-L1. Bioluminescence imaging (BLI) intensities were determined over the course of the study (Day 0 to 26) to assess anti-tumor activity, and tissue was excised at study conclusion to assess fibrosis and immune infiltration. Tumor growth progressed in mice treated with LTF-2 in combination with C or GMI-1757 (final %T/C of 100 and 60.7, respectively), and appeared arrested in mice treated with C and anti-PD-L1 antibody (%T/C = 18.3). In contrast, treatment of tumor-bearing mice with GMI-1757 in combination with anti-PD-L1 antibody resulted in tumor regressions in 5/8 mice with a final %T/C = 0.60. Using a histopathologic scoring system, the extent of fibrosis within the primary pancreatic tumors was dependent on treatment with GMI-1757. Tumor fibrosis was moderate to marked in groups 1 and 3, and minimal to mild in groups 2 and 4. These results were confirmed by morphometric analysis of Masson's Trichrome stained sections where the percent tumor fibrosis area was approximately 29 and 19% in groups 1 and 3, respectively, and 10 and 5% in groups 2 and 4, respectively. Notably, tumor infiltrating immune cells were enhanced with GMI-1757 treatment as compared to C (moderate to marked vs. minimal). The immune phenotypes comprising the increased mononuclear cell infiltration into orthotopic Pan02 tumors continues to be investigated. In summary, we report on the use of a dual E-selectin and galectin-3 antagonist to attenuate fibrosis and enhance mononuclear cell infiltration in an orthotopic model of pancreatic carcinoma. The shifts in fibrotic response and cellular infiltration obtained with GMI-1757 treatment in this model creates a more robust antitumor effect when combined with anti-PD-L1 treatment compared to anti-PD-L1 treatment alone. The impact of GMI-1757 to combine with immune modulators where fibrosis and restricted host cell infiltration negatively impact tumor response continues to be investigated.

Citation Format: William E. Fogler, Theodore A. Smith, Ji-Won Lee, Silvia Locatelli-Hoops, David Stewart, John Peterson, John L. Magnani. A novel glycomimetic compound (GMI-1757) with dual functional antagonism to E-selectin and galectin-3 attenuates fibrosis, facilitates mononuclear cell infiltration and optimizes anti-PD-L1 therapeutic activity in a pancreatic adenocarcinoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB164.