Dobrenkov Konstantin, Olszewska Malgorzata, Likar Yury, Shenker Larissa, Gunset Gertrude, Cai Shangde, Pillarsetty Nagavarakishore, Hricak Hedvig, Sadelain Michel, Ponomarev Vladimir
Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Nucl Med. 2008 Jul;49(7):1162-70. doi: 10.2967/jnumed.107.047324. Epub 2008 Jun 13.
Noninvasive imaging technologies have the potential to enhance the monitoring and improvement of adoptive therapy with tumor-targeted T lymphocytes. We established an imaging methodology for the assessment of spatial and temporal distributions of adoptively transferred genetically modified human T cells in vivo for treatment monitoring and prediction of tumor response in a systemic prostate cancer model.
RM1 murine prostate carcinoma tumors transduced with human prostate-specific membrane antigen (hPSMA) and a Renilla luciferase reporter gene were established in SCID/beige mice. Human T lymphocytes were transduced with chimeric antigen receptors (CAR) specific for either hPSMA or human carcinoembryonic antigen (hCEA) and with a fusion reporter gene for herpes simplex virus type 1 thymidine kinase (HSV1tk) and green fluorescent protein, with or without click beetle red luciferase. The localization of adoptively transferred T cells in tumor-bearing mice was monitored with 2'-(18)F-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-ethyluracil ((18)F-FEAU) small-animal PET and bioluminescence imaging (BLI).
Cotransduction of CAR-expressing T cells with the reporter gene did not affect CAR-mediated cytotoxicity. BLI of Renilla and click beetle red luciferase expression enabled concurrent imaging of adoptively transferred T cells and systemic tumors in the same animal. hPSMA-specific T lymphocytes persisted longer than control hCEA-targeted T cells in lung hPSMA-positive tumors, as indicated by both PET and BLI. Precise quantification of T-cell distributions at tumor sites by PET revealed that delayed tumor progression was positively correlated with the levels of (18)F-FEAU accumulation in tumor foci in treated animals.
Quantitative noninvasive monitoring of genetically engineered human T lymphocytes by PET provides spatial and temporal information on T-cell trafficking and persistence. PET may be useful for predicting tumor response and for guiding adoptive T-cell therapy.
非侵入性成像技术有潜力加强对肿瘤靶向性T淋巴细胞过继性疗法的监测和改进。我们建立了一种成像方法，用于评估过继性转移的基因改造人T细胞在体内的时空分布，以监测系统性前列腺癌模型中的治疗情况并预测肿瘤反应。
在SCID/米色小鼠中建立用人类前列腺特异性膜抗原（hPSMA）和海肾荧光素酶报告基因转导的RM1小鼠前列腺癌肿瘤。用人前列腺特异性膜抗原（hPSMA）或人癌胚抗原（hCEA）特异性嵌合抗原受体（CAR）以及单纯疱疹病毒1型胸苷激酶（HSV1tk）和绿色荧光蛋白的融合报告基因转导人T淋巴细胞，有或没有叩甲红色荧光素酶。用2'-（18）F-氟-2'-脱氧-1-β-D-阿拉伯呋喃糖基-5-乙基尿嘧啶（（18）F-FEAU）小动物正电子发射断层扫描（PET）和生物发光成像（BLI）监测过继性转移的T细胞在荷瘤小鼠中的定位。
表达CAR的T细胞与报告基因共转导不影响CAR介导的细胞毒性。海肾荧光素酶和叩甲红色荧光素酶表达的BLI能够在同一只动物中同时对过继性转移的T细胞和系统性肿瘤进行成像。PET和BLI均显示，hPSMA特异性T淋巴细胞在肺hPSMA阳性肿瘤中比对照hCEA靶向T细胞持续时间更长。PET对肿瘤部位T细胞分布的精确量化显示，延迟的肿瘤进展与治疗动物肿瘤灶中（18）F-FEAU积累水平呈正相关。
通过PET对基因工程人T淋巴细胞进行定量非侵入性监测可提供T细胞运输和持久性的时空信息。PET可能有助于预测肿瘤反应并指导过继性T细胞治疗。
