The strategy to treat cancer by modulating the immune response has been the subject of research for the last twenty years, including the use of vaccines or activating cytokine therapies. Recently, in the last few years, a breakthrough was achieved by the discovery of immune checkpoints, particularly the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programed cell death receptor-1 (PD-1), or programed cell death ligand-1 (PD-L1).
The blockade of the pathway for PD-L1 and PD-1 has been used therapeutically for the treatment of a variety of cancers and has achieved long-term remissions in some patients and there are a number of active clinical trials ongoing that target PD-1 and PD-L1. However, a number of cancers are resistant to checkpoint inhibitor-based immunotherapy. The majority of the drugs used for the blockade of the PD-1 and PD-L1 pathways are humanized antibodies. The fact that there have been immune related toxicities associated with PD pathway blockade using the current technologies suggests that an alternative approach may be necessary.
Researchers at UC San Diego have discovered a method to modulate PD-L1 expression by administering an inhibitor that can be used to prevent the upregulation of PD-L1. IRE1 is a sensor in the Unfolded Protein Response (UPR) Pathway and use of a small molecule inhibitor of IRE1 resulted in the disablement of IRE1 signaling in myeloid cells (dendritic cells and macrophages). This event disables the ability of these cells to respond to activation of the ER stress response with the specific response leading to the transcriptional upregulation of PD-L1 and contextually of proinflammatory cytokines. PD-L1s play a pivotal role in the inactivation of T cell immunity leading to cancer progression/promotion.
The small molecule inhibitor can be used to reduce the level of PD-L1 or the level of PD-L1 activity in a cancer cell or immune cell associated with cancer.
There are no known therapeutic inhibitors of PD-L1 other than antibodies. The invention addresses the mechanism whereby PD-L1 is upregulated. This is a potentially new way to prevent the adverse effects cancer cells have on immune cells, hence promoting their own growth
The current state of development has utilized human cells lines to demonstrate that in bone marrow derived macrophages treated with human colon cancer cell line ER stressed conditioned medium upregulated CD274 (PDL1). This upregulation can be disabled through treatment with the IRE1 inhibitor, but not with the PERK inhibitor GSK2656157.
This technology is patent pending and available for licensing and/or research sponsorship.
immune checkpoint inhibitor, UPOR, therapeutics, cancer, immunmotherapy, PD-L1, PD-1, cancer immunotherapy, cancer