Abstract 1243: Effects of ITI-214, a potent and selective phosphodiesterase type 1 inhibitor, on tumor myeloid cellular composition, tumor volume and survival in mouse models of colorectal cancer when combined with an anti-PD-1 checkpoint inhibitor
Authors: Snyder Gretchen L. , John Peter A. , Pulanco Marc V. , Zang Xingxing , Fienberg Allen A. , Davis Robert E. 
Published: July 2021

Abstract
We investigated the effect of ITI-214, a selective phosphodiesterase type 1 (PDE-1) inhibitor [Li et al., J Med Chem, 2016, 1149-64] on immune cell composition of the tumor microenvironment, tumor volume and survival in syngeneic mouse model of colorectal cancer. The studies are based on our previous preclinical work showing that PDE-1 inhibitors modulate the function of immune cells (microglia, macrophages) by reducing immune cell motility and down-regulating key cytokines (CCL2 and TNFa). We hypothesize that ITI-214 will inhibit macrophage infiltration into the tumor microenvironment and reverse macrophage suppression of immune responses in immunogenic cancers, thereby promoting antitumor immunity and tumor killing. The effects of ITI-214, alone or in combination with sub-effective doses of programmed cell death-1 (PD-1) immune checkpoint inhibitor, were assessed on the growth of CT26 tumor in BALB/c mice. Tumor responses in tumor-bearing mice treated with isotype antibodies (i.e. control group) were compared with groups of mice treated with ITI-214 monotherapy (50mg/kg, i.p. qd, from day 7), a sub-effective dose of anti-PD-1 antibody (150 µg anti-PD-1 RPMI-14, days 7, 11, 14, 17), and a combination of each dose of ITI-214 plus a sub-effective dose of the anti PD-1 antibody. Results showed that only mice receiving the combination of ITI-214 with a sub-effective dose of anti-PD-1 displayed significantly reduced tumor growth (p=0.001). Flow cytometry analysis of tumor-infiltrating immune cells revealed that tumors from ITI-214 monotherapy-treated mice showed significantly decreased numbers of tumor (infiltrating) macrophages which were further decreased in mice receiving the combination treatment. Further, the combination therapy of ITI-214 and anti-PD-1 enhanced anti-tumor immunity by eliciting increased numbers of Natural Killer (NK) cells and TNFa-producing CD4 T-cells. The results suggest that ITI-214 alone reduces numbers of tumor macrophages, an effect which we believe unmasks the anti-tumor immune response induced by anti-PD-1 antibodies. In separate experiments we assessed the effect of combined anti-PD-1 (5mg/kg anti-PD-1 RPMI-14, biwk x 2) and ITI-214 treatment (25 or 50mg/kg, oral, qd, from day 7) on survival; the effect of combined anti-PD-1 and ITI-214 treatment produced a complete response in about 50% of treated mice, translating into a statistically significant effect on survival as compared to control (p=0.001). Together, these studies demonstrate a synergistic ability of ITI-214 and anti-PD-1 to alter the tumor environment and control tumor growth. Translating these findings to humans suggests that ITI-214 may provide a means to expand the utility of immune checkpoint inhibitors in immunogenic tumors.
Citation Format: Gretchen L. Snyder, Peter A. John, Marc V. Pulanco, Xingxing Zang, Allen A. Fienberg, Robert E. Davis. Effects of ITI-214, a potent and selective phosphodiesterase type 1 inhibitor, on tumor myeloid cellular composition, tumor volume and survival in mouse models of colorectal cancer when combined with an anti-PD-1 checkpoint inhibitor [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 1243.