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摘要 BTRC的TR & D 3将开发成像剂来检测炎症和免疫，重点是小 分子PET试剂来监测免疫治疗，这是一个日益增长的医疗需求。长期以来，炎症一直是 被认为是肿瘤生长的促进剂。最近，利用先天和适应性免疫来治疗 通过免疫检查点抑制和疫苗来治疗癌症已经吸引了癌症研究人员的关注 和临床医生一样。我们将开发和传播针对癌症及其 与炎症和免疫的关系，即检查点抑制和补体。免疫 检查点蛋白程序性死亡配体1（PD-L1）及其受体PD-1是癌症的优选靶点 免疫疗法。PD-L1由多种肿瘤表达，其过表达在肿瘤细胞中被诱导， 适应肿瘤浸润的细胞毒性T细胞。PD-L1免疫组化（IHC）是最佳预测生物标志物 用于PD-L1/PD-1靶向治疗的治疗监测。然而，PD-L1 IHC充满了使用 不一致的抗体、肿瘤内和肿瘤间表达的异质性以及有限的生物样本 我们相信非侵入性成像可以提供帮助。此外，尽管承诺免疫 检查点治疗，大多数患者没有反应的原因不明。补体系统是 募集炎性细胞和促进因子释放的中心，这些因子可以促进肿瘤生长， 进展，混淆免疫治疗。我们将合成、验证和传播靶向PD-L1的药物 (Aim 1）和补体受体C3aR和C5aR（Aim 2），其通过其同源肿瘤促进因子结合。 过敏毒素在目标3中，我们将确认-与成像后手术组织相关-当前BTRC电极导线 PD-L1成像剂在接受胰腺癌免疫治疗的患者中的应用 Bloomberg-Kimmel免疫治疗研究所一旦以这种最终的方式得到验证，我们将有信心 将该药剂传播到其他地方进行人体研究。TR & D 3还将作为临床验证核心， 中心，不仅将传播如上所述有价值的新人类代理，而且还将提供前体 和其他药物的标准，允许BTRC IND的交叉引用，并提供分析，以满足不断发展的 推动合作项目和服务对象的需求。