Intra-Cellular Therapies Presents Data on Antitumor Effects of Phosphodiesterase I Inhibition in a Preclinical Colorectal Cancer Model at the 2021 American Association for Cancer Research (AACR) Annual Meeting
Our research has demonstrated that the phosphodiesterase type 1 (PDE1) enzyme modulates the immune system by reducing macrophage and microglial activity with demonstrated effects in neuroinflammatory conditions, cancer and cardiac diseases.
Preclinical findings describing the antitumor effects of PDE1 Inhibitors when administered in conjunction with checkpoint inhibitor immunotherapy are being presented at the
Our PDE1 platform consists of a portfolio of PDE I inhibitors that are being developed for cancer and other diseases.
Title: 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 (Poster 1243).
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Antitumor Agents
The poster describes results from preclinical studies demonstrating that the Company’s selective PDE1 inhibitor, lenrispodun (ITI-214), alters the tumor microenvironment and exhibits compelling anti-tumor activity when combined with a programmed cell death-1 (PD-1) immune checkpoint inhibitor in an animal model of colorectal cancer.
In previous studies we have shown the ability of our PDE1 inhibitors to reduce neuroinflammation. In these studies we discovered a novel intracellular pathway by which the PDE1 enzyme controls the functions of certain immune cells called microglia (brain resident macrophage-like cells). We have shown that inhibition of the activity of these cells by PDE1 inhibitors reduces inflammation in the brain (O’Brien et al., 2018).
Based on our understanding of the role of PDE1 in regulating the function of microglia and macrophages, we hypothesized that PDE1 inhibitors would block the recruitment of immunosuppressive cells (macrophages, monocytes) into the tumor microenvironment (TME) of certain cancers. By inhibiting PDE1, host immune responses may be potentiated leading to inhibition of tumor growth.
At AACR we are reporting on pre-clinical studies demonstrating that lenrispodun alone decreased the numbers of infiltrating macrophages and increased the numbers of natural killer cells in the TME. These effects serve to prevent tumors from evading the host immune system and thereby potentiate the tumor killing activity of checkpoint inhibitors. When lenrispodun and an anti-PD-1 antibody were combined, tumor volumes were significantly reduced and tumor-free survival was significantly increased in a mouse model of colon carcinoma. Importantly, the effect of combining an anti-PD-1 immune checkpoint inhibitor and lenrispodun treatment produced a complete response in about 50% (7/15) of treated mice as compared to 10% (1/10) in anti-PD-1 alone treated mice, 20% (1/5) in the lenrispodun alone group and 0% (0/9) in the control group. This translated into a statistically significant effect on survival for the combination treatment group as compared to control (p=0.001).
Tumor associated macrophages can promote tumor growth in certain cancers. Our experiments indicate PDE1 inhibition prevents the migration and accumulation of monocytes and macrophages in the tumor microenvironment and could represent a novel and broadly applicable approach to the treatment of immune responsive cancers. We are currently evaluating our PDE1 inhibitors in other cancer models and are developing potential biomarkers that may assist in the translation of these data to the treatment of human cancers.
Phosphodiesterase type 1 (PDE1) inhibitor Portfolio
Our PDE1 inhibitor program is focused on diseases in which the PDE1 enzyme is over-expressed and/or abnormal immune cell function contributes to disease pathology providing opportunities to pursue innovative treatments for multiple diseases including Parkinson’s disease, heart failure and other diseases.
Lenrispodun is a potent and selective PDE1 Inhibitor and is the lead compound in the Company’s PDE1 portfolio. Lenrispodun is in development for the treatment of symptoms associated with Parkinson's disease and for the treatment of heart failure. Lenrispodun has been generally well tolerated with a favorable safety profile in six Phase 1 clinical trials. Lenrispodun works by blocking the breakdown of cyclic nucleotides (cAMP, cGMP), thus allowing these molecules to build up in the cells and to exert important functions.
Previous studies have described the mechanism of action of lenrispodun in the brain. The mechanism of action of ITI-214 and our other PDE1 inhibitors suggests therapeutic potential across a variety of diseases including neurological and, cardiovascular diseases and cancer.
About Intra-Cellular Therapies
Intra-Cellular Therapies is a biopharmaceutical company founded on Nobel prize-winning research that allows us to understand how therapies affect the inner-workings of cells in the body. The company leverages this intracellular approach to develop innovative treatments for people living with complex psychiatric and neurologic diseases.
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Vice President, Corporate Communications and Investor Relations
Source: Intra-Cellular Therapies Inc.