Abstract 2577: ITI-214, a potent and selective PDE1 inhibitor, inhibits tumor growth when combined with a checkpoint inhibitor in a mouse model of breast cancer
Authors: Voisin Maud , Goding Stephen , Snyder Gretchen L. , Davis Robert E. 
Published: June 2022

Abstract
Breast cancer is the most common cancer in women. Targeted therapies, such as hormonotherapy or immunotherapy, including checkpoint inhibitors, have revolutionized cancer treatment and are effective for most breast cancer patients. Unfortunately, some patients do not benefit from these therapies and development of resistance might lead to cancer progression in patients with primary clinical responses. Therefore, resistance to checkpoint inhibitor (e.g., PD-1/PD-L) blockade remains a significant challenge and impedes their broader application. To overcome this limitation, development of new therapeutic solutions to improve efficacy and clinical response is essential. We have demonstrated that a selective inhibitor (ITI-214) of the phosphodiesterase type 1 (PDE1) enzyme [Li et al. J Med Chem. 2016;59:1149] modulates immune cell function (microglia and macrophages) by altering cell migration and key cytokines (mainly CCL2 and TNF-α) [O’Brien et al. MCN. 2020;102:103449]. We hypothesized that ITI-214 will affect macrophage infiltration and polarization, as well as improve T cell recruitment and function into the tumor microenvironment, thereby promoting antitumor immunity in murine cancer models. Here we have tested this hypothesis by studying the effect of ITI-214, alone or in combination with sub-effective doses of a programmed cell death-1 (PD-1) immune checkpoint inhibitor, in a syngeneic mouse model of breast cancer. We measured effects of ITI-214 (+/-anti-PD-1 antibody, 10 mpk) on tumor growth, tumor microenvironment composition, and survival of E0771 tumor-bearing C57Bl/6 mice. Tumor growth in mice treated with ITI-214 or with anti-PD-1 antibody alone was similar to isotype control. However, significant inhibition of tumor growth was observed in mice receiving ITI-214 and anti-PD-1 in combination compared to control. Flow cytometry analysis of the tumor microenvironment showed no change in the number of tumor macrophages or T cells in the combination group, but significant shift in the polarization of macrophages toward a more inflammatory phenotype. Furthermore, RNAseq analysis of tumors treated with combination therapy showed a reduction in genes from pathways involved in cell cycle and proliferation and an increase in genes from inflammatory and immune response pathways. The results suggest that ITI-214, in combination with anti-PD-1 antibody, promotes antitumor immunity, leading to tumor growth inhibition. Furthermore, we have evidence that these observations are driven by tumor-associated macrophages. In conclusion, this study demonstrates a synergistic ability of ITI-214 and anti-PD-1 to alter the tumor microenvironment and control tumor growth in mice. Translating these findings to the clinic suggests that ITI-214 may provide a means to expand the utility of immune checkpoint inhibitors to treatment-refractory tumors.
Citation Format: Maud Voisin, Stephen Goding, Gretchen L. Snyder, Robert E. Davis. ITI-214, a potent and selective PDE1 inhibitor, inhibits tumor growth when combined with a checkpoint inhibitor in a mouse model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2577.