Cancer immunotherapy is a novel and rapidly growing field of research investigating the use of therapies that harness the body’s own immune system in the fight against cancer. Tumors utilise a variety of mechanisms to evade host immune detection. There is mounting evidence that some tumor-infiltrating immune cells such as MDSCs, Tregs and TAMs, actively modulate the tumor microenvironment to suppress the effector arms of this response. The aim of the cancer immunotherapy approach is to prevent a tumor’s ability to suppress its own detection and elimination by the host immune system. Ipilimumab (Yervoy®) was the first cancer immunotherapy drug to be approved and has been shown to provide significant survival benefit for malignant melanoma patients. More recently, two monoclonal antibodies each targeting the immune checkpoint PD-1 receptor, Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®), have been approved for metastatic melanoma and metastatic melanoma/squamous non-small cell lung cancer, respectively. A number of additional biologic agents, which target a range of other immune signalling mechanisms, e.g., OX40, LAG-3, KIR, are in clinical development for the treatment of a variety of cancers. Based on recent clinical data, there is growing excitement around the opportunity to provide even greater benefit to cancer patients by combining immunotherapies with each other and with existing cytotoxic and targeted anti-cancer agents.
IOmet’s Novel IDO Inhibitors, TDO Inhibitors & Dual TDO/IDO Inhibitors
The tryptophan catabolism pathway, and its kynurenine-derived metabolites, have emerged as key players in tumor-driven immune suppression and resistance to other immunotherapies. IDO (indoleamine-2,3-dioxygenase) and TDO (tryptophan-2,3-dioxygenase) are the first and rate-limiting enzymes in this pathway. Overexpression of these enzymes has been detected in a variety of cancers, e.g., glioma, melanoma, lung, ovarian and colorectal cancers, and is associated with poor prognosis and survival. IDO and TDO overexpression leads to high tumor levels of kynurenine and downstream metabolites, which suppress effector T cell tumor responses and promote increased numbers of immunosuppressive Treg cells. The combined effect is to facilitate tumor progression and metastasis. Extensive preclinical evidence, and emerging clinical data, suggests that inhibition of IDO and/or TDO may synergise with, and help overcome resistance to, existing clinical immunotherapies.
IOmet has identified multiple series of novel, potent, best-in-class small molecule inhibitors of IDO and TDO. These include highly selective inhibitors at each of these targets, as well as potent dual-acting agents.