Abstract 2619: Combination of ECP1014 and anti-PD-L1 reduces tumor growth in the CT26 murine colon carcinoma model of a cold tumor
Authors: Sandage Bobby W. , Talley John J. , Martinez Eduardo J. , Franklin Maryland R. , Meade Mary Anne , Saims Dan , Thayer Matt , Wise Scott , Draper David , Leopold Wilber 
Published: July 2017

Objective: The objective of this study was to evaluate the effect of ECP1014, a new selective COX2 inhibitor, in combination with a PDL1 inhibitor on tumor growth in a CT26 murine colon carcinoma model. Colon cancer has been described as a “cold tumor” and antiPDL1monotherapy has shown limited or no benefit. In addition, many colon cancer cell lines produce high levels of PGE2, which may in turn dampen the immune system. The hypothesis was that combining ECP1014, which we have shown potently decreases PGE2 in CT26, with a checkpoint inhibitor would increase immune response to the tumor, turning it “hot” and producing superior tumor control versus either agent alone.

Methods: Balb/C mice were implanted with CT26 cells and randomly assigned to 7 treatment groups; vehicle (G1), 10mg/kg rat IgG2b control (G2), 10mg/kg antiPDL1 (G3), 10mg/kg ECP1014 (G4), 10mg/kg ECP1014+10mg/kg rat IgG2b (G5), 10mg/kg ECP1014+10mg/kg antiPDL1 (G6), 1mg/kg ECP1014+10mg/kg antiPDL1(G7). ECP1014 was given daily by oral gavage; rat IgG2b and antiPDL1 (clone 10F.9G2) were administered IP. Treatment was started on day 3 post implant and mice were followed for 16 days. Tumor measurements were taken every 2 to 3 days, and a nonparametric approach was taken to assess the pairwise differences among groups using day 16 tumor volumes. In addition, a responder analysis was used. Tumor infiltrating lymphocytes (TIL) were also assessed by flow cytometry on day 16.

Results: All animals developed tumors. G4 to 7 demonstrated statistically significantly (p&lt;0.05) slowing of tumor growth when compared to vehicle (G1). In particular, G7 produced an 87% suppression of tumor growth compared to vehicle. Three animals in G7 showed regression of tumor growth and one additional animal had no detectable growth until day 16. G6 produced 65% suppression of tumor growth compared to G1. G2 to 5 produced 30, 54, 73 and 50% suppression of tumor growth respectively when compared to G1. G7 had the highest number of responders 75% vs. 62.5% for G6 and G4, with all other groups having &lt; 25% responders. TIL analysis from G4, G6 and G7 also displayed the highest levels of CD8+ Tcells (6.3%, 6.8%, and 6.7% respectively, versus 3.8% for antiPDL1 and 2.5% for vehicle groups).

Summary: ECP1014 alone was superior to antiPDL1 in slowing tumor growth. However, the combination of ECP1014+antiPDL1showed the greatest tumor response and growth suppression and markedly increased CD8+ Tcells infiltrating into the tumor vs. single agent anti-PDL1 treatment.

Citation Format: Bobby W. Sandage, John J. Talley, Eduardo J. Martinez, Maryland R. Franklin, Mary Anne Meade, Dan Saims, Matt Thayer, Scott Wise, David Draper, Wilber Leopold. Combination of ECP1014 and anti-PD-L1 reduces tumor growth in the CT26 murine colon carcinoma model of a cold tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2619. doi:10.1158/1538-7445.AM2017-2619