Imaging T Cell Targeting and Function in Human Cancer

研究项目1(RP1)建立在ICMIC-2项目1和2的进展和成功的基础上。我们的假设是，在去势抵抗的前列腺癌患者中，PSMA导向的T细胞靶向、分布和持久性的结构性和PSMA激活的报告基因成像可以同时进行。该提案的中心主题与我们的ICMIC一致：“癌症生物学与实时、非侵入性成像相结合，应用于个体患者的护理和管理。” 第一阶段临床研究将确定人类受试者的基因改变、PSMA指导的过继T细胞治疗是否导致足够的T细胞激活以及前列腺癌的靶向性和持久性(目标1)。这些新的成像实验涉及双重人类报告基因，以前从未在患有癌症的人类受试者身上进行过。成像结果将与标准的临床治疗反应指标进行比较。同时，我们还将在动物模型中探索酸性肿瘤微环境和高乳酸水平是否会使用独特的成像策略组合对T细胞靶向、激活和持久性产生不利影响(目标2)。我们还将利用我们的新型报告系统在前列腺癌的动物模型中确定PSMA表达的调节是否可以增强PSMA导向的T细胞治疗(目标3)。如果在AIMS 2和AIMS 3中获得阳性结果，类似的研究可以很容易地在患者身上进行。 我们的长期目标是进一步开发独特的过继治疗临床试验，其中包括跟踪和监测患者T细胞激活和持久性的报告成像。我们希望能够解决临床免疫学和免疫治疗中的新问题，包括肿瘤微环境的影响和CAR导向的肿瘤抗原对治疗反应的调节。 这些研究的相关性和影响是：1)想象PSMA的贩运和激活状态 T细胞将为前列腺癌患者的治疗提供实质性的附加值。 该项目开发和验证的成像策略可以很容易地应用于其他癌症，以及其他过继治疗(例如干细胞)方案和非恶性疾病；3)酸性-高乳酸-低氧微环境的影响可能会对T细胞的靶向和激活产生重大的负面影响。这些假说将首先在动物模型中进行探索。 重要的是，检测系统、成像策略和治疗对策可以在未来的患者研究中应用和测试，并可以作为其他癌症的类似研究以及其他疾病的过继干细胞治疗的模型。

Research Project 1 (RP1) builds on the progress and success of Projects 1 and 2 in ICMIC-2. Our hypothesis is that both constitutive and PSMA-activated reporter gene imaging of PSMA directed T cell targeting, distribution and persistence can be performed concurrently in patients with castrate-resistant prostate cancer. The central theme of this proposal is consistent with our ICMIC: "cancer biology integrated with real-time, noninvasive imaging for application in individual patient care and management'. A phase 1 clinical study will determine whether genetically altered, PSMA-directed, adoptive T cell therapy in human subjects results in adequate T cell activation as well as targeting and persistence in prostate cancer (Aim 1). These are novel imaging experiments involving dual human reporter genes, not previously performed in human subjects with cancer. The imaging results will be compared to standard clinical treatment-response measures. In parallel, we will also explore in animal models whether an acidic tumor microenvironment and high lactate levels adversely effect T cell targeting, activation and persistence using a unique combination of imaging strategies (Aim 2). We will also determine in animal models of prostate cancer whether modulation of PSMA expression can enhance PSMA-directed T cell therapy using our novel reporter systems (Aim 3). If positive results in Aims 2 and 3 are obtained, similar studies could be readily performed in patients. Our long-term goals are to further develop unique clinical trials of adoptive therapy that includes reporter imaging to track and monitor T cell activation and persistence in patients. We expect to be able to address novel questions in clinical immunology and immunotherapy, including the effects of the tumor microenvironment and modulation of CAR-directed tumor antigens on treatment response. The relevance and impact of these studies are that: 1) imaging the trafficking and activation status of PSMA directed T cells will provide substantial added value to the management of prostate cancer patients undergoing adoptive T cell therapy; 2) the imaging strategies developed and validated in this project could be readily applied to other cancers, as well as applied in other adoptive therapy (e.g., stem cell) protocols and nonmalignant disease; 3) the effect of an acidic-high lactate-hypoxic microenvironment could have a significant negative impact on T cell targeting and activation. These hypotheses will initially be explored in animal models. Importantly, the assay systems, imaging strategies and therapeutic counter-measures could be applied and tested in future patient studies, and could serve as a model for similar studies in other cancers as well as for adoptive stem cell therapy in other diseases.