During their development tumors acquire the capability to escape immune control. Immune escape is a fundamental trait of cancer but until recently there was little understanding of how it develops. IDO is an enzyme that we and others have found to drive immune escape in tumors, where IDO is often inappropriately switched on. Our progress during the original 3-year grant award established genetic and pharmacological proofs that IDO is essential to support inflammatory carcinogenesis and malignant progression. We now seek to pursue a drug-like series that offers second generation improvements to a lead compound that we brought forward to clinical testing (currently in Phase I/IB trials) as a result of a successful FDA IND application generated in collaboration with academic and government investigators and a biopharma company that outlicensed our IDO intellectual property. Continued pursuit of the work, which our group has pioneered as a radically new cancer immunochemotherapy, will generate clinically applicable IDO inhibitors that stimulate the immune system to attack tumors in an animal in a manner that greatly leverages concomitant standard-of-care chemotherapy or radiotherapy. These second generation compounds will address deficiencies in the present experimental lead compound, which may be appropriate for proof-of-concept experiments in clinic but perhaps less suited as a drug for more general mechanism-based clinical applications. The intellectual thrust of this project will continue address the top priority of the field to improve the treatment of metastatic cancers, where recruiting the patient's own immune system by IDO inhibition in combination with standards of care could offer a low cost, broadly applicable, and highly effective method for disease treatment. PUBLIC HEALTH RELEVANCE: During their development tumors acquire the capability to escape immune control. Immune escape is a fundamental trait of cancer but until recently there was little understanding of how it develops. IDO is an enzyme that we and others have found to drive immune escape by tumors. In the present project, we are moving forward to develop our discovery that drug-like small molecule inhibitors of the IDO enzyme stimulate the immune system to attack tumors in an animal in a manner that synergistically leverages the responses that can be achieved with chemotherapy or radiotherapy. While experimental IDO inhibitors do exist, they may only be suitable for proof-of-concept experiments. Thus, the development of a new generation of IDO inhibitors with superior pharmacological characteristics is highly desirable for clinical application. Our work addresses the major need to improve treatment of disseminated cancers where recruiting the patient's own immune system may offer a generalized and effective method for disease treatment.