Enhancement of T cell therapy by incorporating adjunct treatment strategies

项目总结（与母公司R 01相比无变化） 嵌合抗原受体（CAR）T细胞疗法是MSKCC的一项活跃的基础研究和临床项目， 涉及治疗急性和慢性淋巴细胞白血病（CD 19 CAR特异性）和晚期转移性 前列腺癌（PSMA CAR特异性）自体T细胞。后一项研究包括监测T细胞运输 和124 I-FIAU/18F-FIAU和PET成像的持久性。我们的建议是对这些正在进行的研究的补充 并探索了将免疫调节添加到CAR导向的T细胞疗法中的益处。 我们的主要目标是验证可用于同时监测CAR的报告成像系统。 定向T细胞肿瘤靶向、活化和持久性（组成型报告基因1）和T细胞活化（NFAT-1）。 诱导型报告基因2），加上肿瘤进展或消退（组成型报告基因3），在小动物模型中， 前列腺癌我们还建议开发一种新的转基因小鼠群体， 人PSMA和我们的多报告系统（但在其他方面保留正常的免疫功能）;这种小鼠 集落将宿主原位同源MycCap鼠肿瘤。我们还将研究一个成熟的人类 NOD SCID小鼠中的前列腺（原位）异种移植物。 我们的第二个目标是解决生物学和治疗问题，即， 免疫调节策略可以增强过继性CAR定向T细胞疗法。其中包括：（a）是否 抑制PD-1/PD-1 L受体“检查点”，或是否抑制CXCR 4/CXCL 12信号传导，或 抑制TGFβ1信号传导是否会导致改善的PSMA CAR导向的T细胞靶向、活化和 治疗应答; B）上述免疫调节效应物的联合抑制是否导致免疫应答; 协同改善PSMA CAR导向的T细胞靶向、活化和治疗应答。我们 建议使用报告系统（目的1）和转基因免疫活性宿主动物（目的2）来验证 通过在适当的动物模型中进行实时成像来验证我们的假设。 我们的中心主题和假设是：1）同时成像和监测T细胞肿瘤靶向， 激活和持久性，加上前列腺癌的小动物模型中的肿瘤进展（或消退）， 可行; 2）肿瘤块中的T细胞排除发生在鼠和人前列腺癌动物中 3）免疫调节疗法（如上所述）将逆转T细胞从肿瘤中的排斥， 导致改善的PSMA CAR导向的T细胞肿瘤靶向、活化和治疗反应; 4） 使用上述免疫调节效应物的组合抑制将导致免疫调节的协同改善。 PSMA CAR导向的T细胞肿瘤靶向、活化和治疗反应。还应指出，我们 已经比较了几种基于人类PET的报告系统在转导的人类T细胞中， 适用于未来的临床研究（基于PET的报告基因不是本申请的一部分）。

PROJECT SUMMARY (unchanged from parent R01) Chimeric antigen receptor (CAR) T-cell therapy is an active basic research and clinical program at MSKCC, involving treatment of acute and chronic lymphocyte leukemia (CD19 CAR-specific) and advanced metastatic prostate cancer (PSMA CAR-specific) autologous T cells. The latter study includes monitoring T cell trafficking and persistence with 124I-FIAU/18F-FIAU and PET imaging. Our proposal compliments these on-going studies at MSKCC and explores the benefits of adding immune modulation to CAR-directed T cell therapy. Our primary objective is to validate reporter imaging systems that can be used to concurrently monitor CAR- directed T cell tumor targeting, activation and persistence (constitutive Reporter 1) and T cell activation (NFAT- inducible Reporter 2), plus tumor progression or regression (constitutive Reporter 3) in small animal models of prostate cancer. We also propose to develop a novel transgenic mouse colony that is immune tolerant to human PSMA and our multiple reporter systems (but otherwise retains normal immune function); this mouse colony will host orthotopic syngeneic MycCap murine tumors. We will also study an established human prostate (orthotopic) xenografts in NOD SCID mice. Our secondary objectives are related to addressing biological and therapeutic questions; namely, whether immune modulation strategies can enhance adoptive CAR-directed T cell therapy. They include: a) whether inhibition of the PD-1/PD-1L receptor “check-point”, or whether the inhibition of CXCR4/CXCL12 signaling, or whether inhibition of TGFβ1 signaling results in improved PSMA CAR-directed T cell targeting, activation and treatment response; b) whether combined inhibition of the above immune modulatory effectors results in a synergistic improvement of PSMA CAR-directed T cell targeting, activation and treatment response. We propose to use the reporter systems (Aim 1) and transgenic immune competent host animal (Aim 2) to verify our hypotheses by real-time imaging in appropriate animal models. Our central theme and hypothesis are that: 1) concurrent imaging and monitoring of T cell tumor targeting, activation and persistence, plus tumor progression (or regression) in small animal models of prostate cancer is feasible; 2) T cell exclusion from the tumor mass occurs in both murine and human prostate cancer animal models; 3) Immune modulation therapy (described above) will reverse T cell exclusion from the tumor and result in improved PSMA CAR-directed T cell tumor targeting, activation and treatment response; 4) Combined inhibition, using the above immune modulatory effectors, will result in a synergistic improvement of PSMA CAR-directed T cell tumor targeting, activation and treatment response. It should also be noted that we have compared several human PET-based reporter systems in transduced human T cells that would be suitable for future clinical studies (the PET-based reporters are not part of this application).