IDO inhibitors for combinatorial cancer therapy

描述(申请人提供)：肿瘤在发育过程中获得逃避免疫控制的能力。免疫逃逸是癌症的一个基本特征，但直到最近，人们对它是如何发展的还知之甚少。IDO是一种酶，我们和其他人已经发现它可以在肿瘤中驱动免疫逃逸，在肿瘤中，IDO经常被不适当地激活。我们在最初的3年资助奖中取得的进展建立了遗传和药理学证据，证明IDO对于支持炎症性癌症的发生和恶性进展是必不可少的。我们现在正在寻求一种类似药物的系列，对我们提前进行临床测试(目前处于I/IB阶段试验)的先导化合物进行第二代改进，这是FDA与学术和政府研究人员合作成功申请IND的结果，也是一家生物制药公司获得IDO知识产权授权的结果。这项工作是我们团队作为一种全新的癌症免疫化疗而开创的，继续进行这项工作将产生临床适用的IDO抑制剂，这种抑制剂可以刺激免疫系统攻击动物体内的肿瘤，其方式很大程度上利用了伴随的标准护理化疗或放射治疗。这些第二代化合物将解决目前实验先导化合物的不足，这些先导化合物可能适合于临床上的概念验证实验，但可能不适合作为更一般的基于机制的临床应用的药物。该项目的智力主旨将继续解决改善转移性癌症治疗这一领域的首要任务，通过IDO抑制结合护理标准招募患者自身的免疫系统可以提供一种低成本、广泛适用和高效的疾病治疗方法。

DESCRIPTION (provided by applicant): 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.