IDO inhibitors for combinatorial cancer therapy

用于组合癌症治疗的 IDO 抑制剂

• 批准号: 8206194
• 负责人: GEORGE C PRENDERGAST
• 金额: $ 26.06万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206194
• 关键词: Address; Animals; Award; Biochemical; Biological Assay; Cancer Patient; Caring; Cells; Characteristics; Clinic; Clinical Trials; Collaborations; Computer Simulation; Cytotoxic Chemotherapy; Development; Disease; Disseminated Malignant Neoplasm; Enzymes; Evolution; Generations; Genetic; Goals; Government; Grant; Immune; Immune system; Immunologic Surveillance; In Vitro; Inflammatory; Intellectual Property; Lead; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Modeling; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Radiation therapy; Recruitment Activity; Research Personnel; Series; T-Lymphocyte; Translations; Tryptophan 2,3 Dioxygenase; Tumor Escape; Work; base; cancer immunotherapy; cancer therapy; carcinogenesis; chemotherapy; clinical application; combinatorial; cost; improved; in vivo; inhibitor/antagonist; neoplastic cell; pre-clinical; programs; research clinical testing; research study; response; small molecule; standard of care; trait; tumor; tumor growth

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. 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.

描述（由申请人提供）：在其发育过程中，肿瘤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，在肿瘤中驱动免疫逃逸，IDO经常被不适当地打开。我们在最初的3年资助期间取得的进展建立了遗传学和药理学证据，证明IDO对支持炎性致癌和恶性进展至关重要。我们现在寻求一个类似药物的系列，为我们提出临床试验（目前处于I/IB期试验）的先导化合物提供第二代改进，这是由于与学术和政府调查人员以及一家生物制药公司合作成功地提出了FDA IND申请，该公司获得了我们IDO知识产权的许可。继续追求这项工作，我们的团队已经率先作为一种全新的癌症免疫化疗，将产生临床适用的IDO抑制剂，刺激免疫系统以极大地利用伴随的标准治疗化疗或放疗的方式攻击动物中的肿瘤。这些第二代化合物将解决本实验先导化合物中的缺陷，其可能适合于临床中的概念验证实验，但可能不太适合作为基于更一般机制的临床应用的药物。该项目的智力推力将继续解决该领域的首要任务，以改善转移性癌症的治疗，其中通过IDO抑制结合护理标准招募患者自身的免疫系统可以提供低成本，广泛适用和高效的疾病治疗方法。 公共卫生相关性：在肿瘤的发展过程中，肿瘤获得了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驱动肿瘤的免疫逃逸。在本项目中，我们正在向前发展我们的发现，即IDO酶的药物样小分子抑制剂刺激免疫系统以协同利用化疗或放疗可以实现的反应的方式攻击动物中的肿瘤。虽然实验性IDO抑制剂确实存在，但它们可能仅适用于概念验证实验。因此，开发具有上级药理学特征的新一代IDO抑制剂对于临床应用是非常期望的。我们的工作解决了改善播散性癌症治疗的主要需求，其中招募患者自身的免疫系统可以为疾病治疗提供普遍有效的方法。