Imaging Agents for Inflammatory Components of Malignancy

研发总结3 BTRC的研发3将开发用于检测炎症和免疫的显像剂，重点是小分子 用于监测免疫治疗的分子PET试剂，日益增长的医疗需求。长期以来，炎症一直是 被公认为是肿瘤生长的促进剂。最近，利用先天和获得性免疫来治疗 通过免疫检查点抑制和疫苗的癌症已经吸引了癌症研究人员的社区 和临床医生一样。我们将开发和传播针对癌症和其两个不同方面的药物 与炎症和免疫的关系，即检查点抑制和补体。免疫者 检查点蛋白程序性死亡配体1及其受体PD-1是肿瘤的首选靶点 免疫疗法。PD-L1在多种肿瘤中均有表达，其过表达可诱导肿瘤细胞 适应肿瘤浸润性细胞毒性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靶向治疗的治疗监测。然而，PD-L1 IHC充满了对 不一致的抗体、瘤内和瘤间表达的异质性以及有限的生物标本 可用性使我们相信非侵入性成像可以提供帮助。此外，尽管有免疫的承诺 在检查点疗法中，大多数患者因不明原因而没有反应。补语系统是 募集炎性细胞和促进释放可促进肿瘤生长和 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)，它们由它们的同源促肿瘤作用结合 过敏毒素。在目标3中，我们将验证-与成像后手术组织相关-当前的BTRC导联 PD-L1显像剂在胰腺癌免疫治疗患者中的应用 彭博-基梅尔免疫疗法研究所。一旦以这种终极方式进行验证，我们将有信心 将这种用于人体研究的媒介传播到其他地方。研发3也将作为临床验证核心，一个 中心不仅将传播如上所述的有价值的新的人类媒介，而且还将提供前体 和其他代理的标准，允许交叉引用BTRC IND，并提供分析以满足不断发展的 推动协作项目和服务接受者的需求。

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.