Imaging Agents for Inflammatory Components of Malignancy

恶性肿瘤炎症成分的显像剂

• 批准号: 10226210
• 负责人: MARTIN G POMPER
• 金额: $ 25.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226210
• 关键词: Address; Affinity; Anaphylatoxins; Anatomy; Antibodies; Automobile Driving; Binding; Breast; C3AR1 gene; CAR T cell therapy; Cells; Cessation of life; Clinic; Clinical; Communities; Complement; Complement Receptor; Cyclic GMP; Cytotoxic T-Lymphocytes; Data; Data Analyses; Disease; Doctor of Medicine; Doctor of Philosophy; Failure; Funding; Human; Image; Image-Guided Surgery; Immune; Immunity; Immunohistochemistry; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Institutes; Inter-tumoral heterogeneity; Label; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Medical; Medical Oncology; Molecular Weight; Monitor; Natural Immunity; Neoadjuvant Therapy; Neuraxis; New Agents; Non-Invasive Cancer Detection; Non-Small-Cell Lung Carcinoma; Pathologic; Patients; Peptides; Play; Positron-Emission Tomography; Process; Property; Proteins; Reagent; Reporting; Research Personnel; Resources; Role; Series; Services; Site; Specificity; Structure; Techniques; Therapeutic; Therapeutic antibodies; Tissues; Toxic effect; Translating; Tumor Promoters; Tumor-infiltrating immune cells; Vaccines; Validation; adaptive immunity; analog; base; cancer immunotherapy; cannabinoid receptor; checkpoint inhibition; checkpoint therapy; complement system; first-in-human; imaging agent; immune checkpoint; in vivo; interest; macrophage; malignant breast neoplasm; molecular imaging; mouse model; neoplastic cell; neuroinflammation; next generation; non-invasive imaging; overexpression; pancreatic cancer patients; pre-clinical; precision medicine; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; radiotracer; receptor; recruit; release factor; side effect; small molecule; success; targeted agent; targeted imaging; targeted treatment; therapeutic target; treatment response; tumor; tumor growth; tumor progression; user-friendly; validation studies

SUMMARY FOR TR&D 3 TR&D 3 of the BTRC will develop imaging agents to detect inflammation and immunity, with a focus on small molecule PET agents to monitor immunotherapy, an increasing medical need. Inflammation has long been recognized as a promoter of tumor growth. More recently, harnessing innate and adaptive immunity to treat cancer through immune checkpoint inhibition and vaccines has captivated the community of cancer researchers and clinicians alike. We will develop and disseminate agents that address two different aspects of cancer and its relationships to inflammation and immunity, namely, checkpoint inhibition and complement. The immune checkpoint protein programmed death-ligand 1 (PD-L1) and its receptor PD-1 are preferred targets for cancer immunotherapy. PD-L1 is expressed by a variety of tumors, and its over-expression is induced in tumor cells to adapt to tumor infiltrating cytotoxic T cells. PD-L1 immunohistochemistry (IHC) is the best predictive biomarker for therapeutic monitoring of PD-L1/PD-1 targeted therapies. However, PD-L1 IHC is fraught with use of discordant antibodies, intra- and inter-tumoral heterogeneity of expression as well as limited bio-specimen availability such that we believe non-invasive imaging can help. Furthermore, despite the promise of immune checkpoint therapy, the majority of patients do not respond for reasons unclear. The complement system is central to recruiting inflammatory cells and promoting release of factors that can promote tumor growth and progression, confounding immunotherapy. We will synthesize, validate and disseminate agents targeting PD-L1 (Aim 1) and complement receptors C3aR and C5aR (Aim 2), which are bound by their cognate tumor-promoting anaphylatoxins. In Aim 3 we will validate – with correlation to post-imaging surgical tissue – a current BTRC lead PD-L1 imaging agent in patients undergoing immunotherapy for pancreas cancer through support from the Bloomberg-Kimmel Institute for Immunotherapy. Once validated in this ultimate fashion we will be confident to disseminate that agent for human studies elsewhere. TR&D 3 will also serve as the Clinical Validation Core, a hub that will disseminate not only valuable new human agents as noted above, but will also provide precursor and standard for other agents, allow cross-referencing of BTRC INDs and provide analysis to meet the evolving needs of the driving Collaborative Projects and service recipients.

TR＆D 3的摘要 BTRC的TR＆D 3将开发成像剂以检测注射和免疫力，重点是小 分子宠物药物以监测免疫疗法，这是医疗需求的增加。炎症长期以来一直是 被公认为是肿瘤生长的启动子。最近，利用先天和适应性免疫学来治疗 通过免疫切除点抑制和疫苗吸引了癌症研究人员社区 和临床医生。我们将开发并传播针对癌症及其癌症两个不同方面的药物 与炎症和免疫史的关系，即检查点抑制和完成。免疫 检查点蛋白编程的死亡配体1（PD-L1）及其接收器PD-1是癌症的首选目标 免疫疗法。 PD-L1由多种肿瘤表达，其过表达在肿瘤细胞中诱导 适应肿瘤浸润的细胞毒性T细胞。 PD-L1免疫组织化学（IHC）是最好的预测生物标志物 用于PD-L1/PD-1靶向疗法的热监测。但是，PD-L1 IHC是通过使用的 不一致的抗体，表达的内部和肿瘤间异质性以及有限的生物特异性 可用性使我们认为非侵入性成像可以提供帮助。此外，请做免疫的承诺 检查点疗法，大多数患者没有反应，原因不清楚。完成系统是 招募炎症细胞和促进可以促进肿瘤生长和的因素释放的中心 进展，混淆免疫疗法。我们将合成，验证和传播针对PD-L1的药物 （AIM 1）和补体受体C3AR和C5AR（AIM 2），它们受其同源肿瘤的约束 过敏毒素。在AIM 3中，我们将验证与现象后手术组织相关 - 当前的BTRC铅 在接受免疫疗法治疗胰腺癌的患者中的PD-L1成像剂通过 彭博 - 金梅尔免疫疗法研究所。一旦以这种最终的方式进行验证，我们将有信心 在其他地方传播该药物以进行人类研究。 TR＆D 3也将作为临床验证核心，A 枢纽将不仅可以传播如上所述的有价值的新人代理，还将提供前体 和其他代理的标准，允许BTRC IND的交叉引用并提供分析以满足不断发展的 驾驶协作项目和服务收件人的需求。