PET Imaging of Genetically Modified Human T-Cells in Prostate Cancer

这是对PAR-04-069的回应，是基于在原定期间开始的工作的续期申请 ICMIC在MSKCC的资助这项新提案的中心主题是将我们已有的进展转化为 在肿瘤学方面的临床研究和应用。提出了两个重点领域，这两个领域建立在 过去资助期的成功：a)将开发人类报告基因结构并用于研究 以及更好地了解患者过继T细胞治疗中T细胞的相互作用和激活 和2)，以及b)与评估药物治疗反应相关的关键分子的分子成像， 特别是信号转导抑制剂，特别是实体肿瘤(项目3-5)。报告基因 影像在过继细胞治疗中的应用，包括靶向CD4和CDS亚型和嵌合T细胞 对前列腺癌具有人工反应的T细胞，将在人类身上进行研究，使用人类来源的 报告基因(P1和P2)：EBV相关淋巴瘤过继治疗中T细胞相互作用的成像 (R.Blasberg，项目1负责人；R.O‘Rielly，共同负责人)，以及存活、激活和 基因重定向前列腺特异性T细胞对细胞因子刺激的反应(V.Ponomarev，项目2 领导人；M.Sadelain，共同领导人)。在项目3中，高场MRI/MRS将探索体内的药效学 药物转化和代谢，以预测一类重要的新血管生成抑制剂的敏感性， 以及开发非侵入性标记(J·库彻，项目3负责人)。在项目4和项目5中，正电子 基于发射断层扫描(PET)的分子成像方法将研究治疗的生物学 使用雄激素受体、HER2和热休克蛋白90的新型放射配基进行反应。这个 新型信号转导抑制剂作用的体内成像方法研究进展 翻译到临床(N.Rosen，项目3负责人；D.Solit，联合负责人)和分子成像 耐去势转移性前列腺癌(S.Larson，项目5负责人；H.Scherand P.Smith-Jones，Coleaders)。 翻译发展项目、基于肿瘤学的职业发展和分子生物学， 放射化学/回旋加速器和数据分析研究资源提供了必要的基础设施。在……里面 总结，新的分子成像范例将被用于解决重要的临床问题 肿瘤学。

This response to PAR-04-069, is a renewal application based on work begun during the original period of ICMIC funding at MSKCC The central theme of this new proposal is translation of the progress we have made into clinical research and application in oncology. Two focus areas are proposed which build on the success of the past funding period: a) human reporter gene constructs will be developed and used to study and better understand T cell interactions and activation in adoptive T cell therapy in patients, (Projects 1 and 2), and b) molecular imaging of the key molecules relevant to assessing drug treatment response, particularly for signal transduction inhibitors, and especially in solid tumors (Projects 3-5). Reporter gene imaging applications in adoptive cell therapy, including targeting of CD4 and CDS sub-types and chimeric Tcells with T-cells with artificial reactivity to prostate cancer, will be studied in man using human derived reporter genes(P1 and P2): Imaging T cell interactions in adoptive therapy of EBV-associated lymphoma (R. Blasberg, Project 1 leader; R. O'Rielly, co-leader), and PET imaging of survival, activation, and response to cytokine stimulation of genetically retargeted prostate specific T cells (V. Ponomarev, Project 2 leader; M. Sadelain, co-leader). In Project 3, high field MRI/MRS will probe the pharmacodynamics of in vivo drug conversion and metabolism, to predict sensitivity for an important new class of angiogenesis inhibitors, and to develop of non-invasive markers (J. Koutcher, Project 3 leader). In Projects 4 and 5, Positron Emission Tomography (PET) based molecular imaging methods will study the biology of treatment response, using novel radioligands for androgen receptor, her2, and heat shock protein 90. The development of methodologies for the in vivo imaging of the effects of novel inhibitors of signal transduction for translation to the clinic (N. Rosen, Project 3 leader; D. Solit, co-leader), and molecular imaging of castrate-resistant metastatic prostate cancer (S. Larson, Project 5 leader; H. Scherand P. Smith-Jones, coleaders). Translational developmental projects, oncology based career development, and molecular biology, radiochemistry/cyclotron and data analysis research resources provide essential infrastructure. In summary, novel molecular imaging paradigms will be used to address important clinical questions in oncology.