IDO Pathway Inhibitors
Small-molecule, Anti-toleragenic Drugs
NewLink is a leader in the discovery and development of small-molecule, anti-toleragenic drugs to thwart tumor immune escape. Our formulation of 1-methyl-d-tryptophan (D-1MT) is advancing in two Phase 1 clinical trials. D-1MT is a small-molecule that inhibits the activity of IDO as a tolerance-inducing mechanism employed by almost all tumor types. The compound is orally bioavailable, possesses an outstanding preclinical safety profile, and has been shown to be synergistic with many chemotherapeutic agents as well as radiation therapy. We also have a program underway to identify and optimize novel compounds for development as more selective, second-generation inhibitors of IDO.
Why IDO?
IDO is an enzyme that regulates immune response by suppressing effector T-cell function through catabolism of the essential amino acid tryptophan. This serves as a mechanism of acquired peripheral tolerance in a number of focused settings, and in the normal physiologic state IDO plays an important role in limiting the collateral damage to tissue that can than result from an unchecked immune response. IDO's immunoregulatory function was first established by collaborators of NewLink, who identified placental expression of the enzyme as an essential contributor to maternal tolerance toward the fetus. Recent studies have demonstrated that IDO is also overexpressed in many cancers, within both 1) tumor cells as a direct defense against T-cell attack, and also 2) antigen presenting cells in tumor draining lymph nodes (where IDO promotes peripheral tolerance to tumor antigens). When hijacked by developing cancers in this manner, IDO facilitates the survival, growth, invasion, and metastasis of malignant cells expressing TAAs that would normally be recognized and attacked as foreign. Emerging evidence suggests that IDO-mediated tolerization constitutes a preferred nodal pathway for immune escape in enablement of cancer progression.
IDO inhibitors and chemotherapy
Cytotoxic chemotherapy places substantial stress on established, tumor-induced tolerance. Several factors can potentially contribute to this result: 1) dying tumors cells release waves of TAAs for processing and presentation, 2) many chemotherapeutic regimens induce a period of transient lymphopenia and homeostatic recovery during which T-cells may become more susceptible to breaking tolerance, and 3) certain regimens can transiently deplete or inactivate tumor-protective T-regulatory cells. Despite producing these challenges to tolerance, most chemotherapeutic agents do not appear to trigger a protective immune response against established tumors. This shortcoming of traditional chemotherapy has been attributed in significant part to the ability of tumors to rapidly reestablish tolerance following each cycle of chemotherapy. A probable mechanism underlying the failed opportunity is IDO expression by APCs in tumor-draining lymph nodes, which are thereby converted to an immunosuppressive and tolerance-inducing milieu.
The hypothesis suggested above is amply supported by preclinical research. Administration of D-1MT in combination with a variety of cytotoxic chemotherapeutic agents in several models of cancer has elicited regression of established tumors refractory to single-agent therapy. In the MMTV-neu/HER2 transgenic mouse model of breast cancer, immune depletion of CD+4 or CD+8 T-cells before treatment eliminated efficacy of the combination regimen, confirming that D-1MT acted through a T-cell mediated pathway. Significantly, the synergistic anti-tumor effects were not accompanied by any observed increase in toxicity in mice receiving both agents.
Breakthrough potential
Inhibition of the IDO pathway holds potential to enable profound improvement in patient outcomes across a broad range of tumor types and treatment regimens, including combined administration with cytotoxic chemotherapeutic agents, radiation, targeted molecular therapies, and other immunotherapeutic agents (e.g., cancer vaccines). A workshop convened by the National Cancer Institute in July 2007 for the purpose of identifying agents with high potential to serve as immunotherapeutic drugs included D-1MT in its Top 10 ranking of candidates. (The published proceedings of the workshop may be downloaded at web.ncifcrf.gov/research/brb/workshops.asp.)