Notice of Publication of Article on Immune Checkpoint Inhibitory Effect of PAI-1 Inhibitor RS5614

We are pleased to announce that a paper on the immune checkpoint inhibitory effect of the PAI-1 inhibitor RS5614 has been published in the scientific journal “Frontiers in immunology”.
Ibrahim AA, Fujimura T, Uno T, Terada T, Hirano K, Hosokawa H, Ohta A, Miyata M, Ando K, Yahata T.
Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1
Frontiers in immunology 2024 online. (

The basic treatment for cancer is (1) surgical therapy, (2) radiation therapy, (3) chemotherapy (anticancer drugs), and (4) immunotherapy (immune checkpoint inhibitors). The human body has a system called immunity that protects the body from foreign viruses, bacteria, and microbes. The body is equipped with immune checkpoint molecules*1 that suppress excessive immunity. Cancer abuses these immune checkpoint molecules to prevent the immune system from working against itself. Immune checkpoint inhibitors*2 inhibit these immune checkpoint molecules, thereby releasing the brakes and allowing the immune system to attack cancer. Nivolumab, an antibody therapeutic that targets an immune checkpoint molecule called programmed cell death-1 (PD-1), and ipilimumab, an antibody therapeutic that targets an immune checkpoint molecule called cytotoxic T lymphocyte antigen-4 (CTLA-4), are representative immune checkpoint inhibitors used to treat various types of cancer.

It has been long known that the higher the expression of plasminogen activator inhibitor 1 (PAI-1) in cancer tissues, the poorer the prognosis of cancer, (“PAI-1 paradox”), but the mechanism was unclear.

In collaboration with Tokai University and Tohoku University, we have discovered that PAI-1 induces the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint molecule, in various cancer cells and cells infiltrating cancer tissues and interferes with immune response; and conversely, RS5614, a PAI-1 inhibitor, inhibits PD-L1 expression and stimulates immune response. The paper was published in the scientific journal “Frontiers in immunology”. In colorectal cancer models, RS5614 inhibited tumor growth by activating anti-tumor immunity, and showed synergistic anti-tumor effects when combined with an existing immune checkpoint inhibitor, an anti-PD-1 antibody. RS5614 promote the infiltration of cytotoxic T lymphocytes to the tumor tissues, and inhibited the infiltration of regulatory T cells, M2 macrophages, and cancer-associated fibroblasts, which all suppress cancer immunity. Thus, RS5614 shows antitumor effects by improving the immune environment in cancer tissues. This action is an important finding as one of the mechanisms of the PAI-1 paradox.

Based on the immune checkpoint inhibitory action of RS5614, a phase II investigator-initiated clinical trial (“Study”) to investigate the efficacy and safety of RS5614 in combination with nivolumab in patients with unresectable malignant melanoma (melanoma) was conducted in collaboration with Tohoku University Hospital, University of Tsukuba Hospital, Tokyo Metropolitan Komagome Hospital, Nagoya City University Hospital, Kinki University Hospital, and Kumamoto University Hospital. As a result, the efficacy and safety of the combination of RS5614 and nivolumab were confirmed in the second-line treatment of malignant melanoma refractory to nivolumab (response rate: 24.1%; serious adverse events: 5.9%, disclosed on February 22, 2024).

The combination of nivolumab and ipilimumab is approved for the second-line treatment of nivolumab-refractory malignant melanoma, and the Study showed that the combination of nivolumab and RS5614 was as effective or more effective than this existing therapy. In addition, more than half of patients receiving nivolumab in combination with ipilimumab experienced severe immune-related side effects that resulted in discontinuation of treatment, four times more frequently than with nivolumab alone, requiring hospitalization and cessation of cancer treatment for several months. Thus, RS5614, as a nivolumab combination drug with superior efficacy and safety, is useful in the treatment of unresectable malignant melanoma, and, unlike antibody therapeutics, it is a small molecule drug that can be administered orally, making it economically feasible and convenient.

Following the confirmation of the efficacy and safety of RS5614 in the Study, we have also initiated phase II investigator-initiated clinical trials for other solid tumors such as non-small cell lung cancer*3 and cutaneous angiosarcoma*4 based on the immune checkpoint inhibitory action of RS5614 (non-small cell lung cancer, initiated in September 2023; cutaneous angiosarcoma, initiated in October 2023).

1 Immune checkpoint molecules

Immune checkpoint molecules are a group of molecules that inhibit the immune response to self and suppress excessive immune response in order to maintain immune homeostasis. Immune checkpoint molecules exist to prevent lymphocytes from attacking the self by suppressing their excessive activation, but cancer cells abuse immune checkpoint molecules to evade attacks from the immune system. Various immune checkpoint molecules such as PD-1 and CTLA-4 have been identified.

2 Immune checkpoint inhibitors

All drugs currently used as therapeutic agents are antibody therapeutics that bind directly to immune checkpoint molecules and inhibit them.

3 Non-small cell lung cancer

The number of people newly diagnosed with lung cancer has been increasing every year, and in 2018 it was estimated that about 123,000 people (about 82,000 men and 41,000 women) were newly diagnosed with lung cancer, making it the most common cancer among all cancers in terms of deaths. About 80% of lung cancers are non-small cell lung cancer. First-line treatment for advanced non-small cell lung cancer patients who do not have mutations in the driver genes (genes that play a direct role in cancer development and progression) includes platinum-based chemotherapy and immune checkpoint inhibitory antibodies, but the number of cases that are cured is small. Second-line chemotherapy such as docetaxel is used as second-line treatment, but the stable condition is as short as 3 months, and third-line treatment is required. The combination of nivolumab and ipilimumab, both of which are immune checkpoint inhibitory antibodies, is an option for third-line treatment, but it is problematic because of the increased incidence of immune-related side effects and the high medical costs associated with using two antibodies. Based on the immune checkpoint inhibition properties of RS5614, a phase II investigator-initiated clinical trial has been conducted since September 26, 2023 in collaboration with Hiroshima University and other institutions to evaluate the combination of nivolumab and RS5614 in patients with unresectable advanced or recurrent non-small cell lung cancer who have received at least two prior chemotherapies (third-line treatment).

4 Cutaneous angiosarcoma

Cutaneous angiosarcoma is a cancerous transformation of the inner cells of blood vessels (vascular endothelial cells). Angiosarcomas are extremely rare but highly malignant tumors of soft tissue. PAI-1 is strongly expressed on vascular endothelial cells, and its tumor, angiosarcoma, also expresses high levels of PAI-1. It has been reported that patients with high expression of PAI-1 are less likely to respond to taxane anticancer agents used in first-line therapy. Taxane anticancer drugs induce apoptosis, a type of cell death, in angiosarcoma, but cancer cells that express high levels of PAI-1 are less likely to undergo apoptosis. Therefore, it is strongly suggested that the combination of taxane anticancer drugs and a PAI-1 inhibitor, RS5614, may enhance the therapeutic effect of taxane anticancer drugs on angiosarcoma. A phase II investigator-initiated clinical trial to evaluate the efficacy and safety of paclitaxel in combination with RS5614 in patients with cutaneous angiosarcoma who have failed paclitaxel, a taxane anticancer drug, is ongoing from October 26, 2023.