PDF(Pubmed)
Abstract：
UNASSIGNED: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response.
UNASSIGNED: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16).
UNASSIGNED: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted.
UNASSIGNED: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies.
UNASSIGNED: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.
UNASSIGNED: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16).
UNASSIGNED: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted.
UNASSIGNED: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies.
UNASSIGNED: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.
摘要：
■Delta样配体3（DLL3）在许多神经内分泌癌症（包括小细胞肺癌（SCLC）和神经内分泌前列腺癌（NEPC））中的细胞表面异常表达。靶向DLL3的几种治疗剂正在积极的临床开发中。DLL3的分子成像将使得非侵入性诊断评估能够告知DLL3靶向治疗剂的使用或评估疾病治疗反应。
■我们在18例神经内分泌癌患者中对[89Zr]Zr-DFO-SC16.56进行了首次人类免疫正电子发射断层扫描（免疫PET）成像研究，该研究由与去铁胺（DFO）和正电子发射放射性核素锆89缀合的抗DLL3抗体SC16.56组成。最初的三名患者接受了1-2mCi的[89Zr]Zr-DFO-SC16.56，总质量剂量为2·5mg，并在一周的时间内接受了连续的PET和计算机断层扫描（CT）成像。放射性示踪剂间隙,肿瘤摄取，和辐射剂量测定进行了估计。使用初始活动和质量剂量对15名额外患者的扩展队列进行成像。通过免疫组织化学(IHC)评估回顾性收集的肿瘤活检的DLL3(n=16)。
■最初的3名SCLC患者的成像显示[89Zr]Zr-DFO-SC16.56的强烈肿瘤特异性摄取,在注射后第3、4和7天具有相似的肿瘤:背景比。血清清除是双相的，估计末端清除半衰期为119小时。背景示踪剂摄取最高的部位是血池和肝脏。接受最高辐射剂量的正常组织是肝脏；1·8mGy/MBq，有效剂量为0.49mSv/MBq。肿瘤摄取在患者之间和患者内部都有所不同，在解剖部位，SUVmax范围很广(从3·3到66·7)。[89Zr]Zr-DFO-SC16.56的肿瘤摄取与所有病例的蛋白表达相关。通过PET扫描的两个非活跃DLL3NEPC病例通过肿瘤免疫组织化学显示出最低的DLL3表达。只有一个病人有1级过敏反应,而没有发现≥2级不良事件。
■对神经内分泌癌患者进行DLL3PET成像是安全可行的。这些结果证明了[89Zr]Zr-DFO-SC16.56用于非侵入性体内检测表达DLL3的恶性肿瘤的潜在效用。
■由NIHR01CA213448(JTP)支持，R35CA263816(CMR),U24CA213274(CMR),R35CA232130(JSL),和前列腺癌基金会战术奖（JSL），Scannell基金会.放射化学和分子成像探头核心设施由NIHP30CA08748支持。
■我们在18例神经内分泌癌患者中对[89Zr]Zr-DFO-SC16.56进行了首次人类免疫正电子发射断层扫描（免疫PET）成像研究，该研究由与去铁胺（DFO）和正电子发射放射性核素锆89缀合的抗DLL3抗体SC16.56组成。最初的三名患者接受了1-2mCi的[89Zr]Zr-DFO-SC16.56，总质量剂量为2·5mg，并在一周的时间内接受了连续的PET和计算机断层扫描（CT）成像。放射性示踪剂间隙,肿瘤摄取，和辐射剂量测定进行了估计。使用初始活动和质量剂量对15名额外患者的扩展队列进行成像。通过免疫组织化学(IHC)评估回顾性收集的肿瘤活检的DLL3(n=16)。
■最初的3名SCLC患者的成像显示[89Zr]Zr-DFO-SC16.56的强烈肿瘤特异性摄取,在注射后第3、4和7天具有相似的肿瘤:背景比。血清清除是双相的，估计末端清除半衰期为119小时。背景示踪剂摄取最高的部位是血池和肝脏。接受最高辐射剂量的正常组织是肝脏；1·8mGy/MBq，有效剂量为0.49mSv/MBq。肿瘤摄取在患者之间和患者内部都有所不同，在解剖部位，SUVmax范围很广(从3·3到66·7)。[89Zr]Zr-DFO-SC16.56的肿瘤摄取与所有病例的蛋白表达相关。通过PET扫描的两个非活跃DLL3NEPC病例通过肿瘤免疫组织化学显示出最低的DLL3表达。只有一个病人有1级过敏反应,而没有发现≥2级不良事件。
■对神经内分泌癌患者进行DLL3PET成像是安全可行的。这些结果证明了[89Zr]Zr-DFO-SC16.56用于非侵入性体内检测表达DLL3的恶性肿瘤的潜在效用。
■由NIHR01CA213448(JTP)支持，R35CA263816(CMR),U24CA213274(CMR),R35CA232130(JSL),和前列腺癌基金会战术奖（JSL），Scannell基金会.放射化学和分子成像探头核心设施由NIHP30CA08748支持。
