背景:Delta样配体3(DLL3)在小细胞肺癌(SCLC)和神经内分泌前列腺癌细胞的表面异常表达。我们评估了DLL3靶向成像示踪剂[89Zr]Zr-DFO-SC16.56(由与p-SCN-Bn-去铁胺[DFO]缀合的抗DLL3抗体SC16.56作为锆-89的螯合剂组成)的安全性和可行性神经内分泌衍生癌症患者。
方法:我们进行了开放标签,[89Zr]Zr-DFO-SC16.56免疫PET-CT成像的首次人体研究。这项研究是在纪念斯隆·凯特琳癌症中心进行的,纽约,NY,美国。年龄在18岁或以上的经组织学证实的神经内分泌衍生恶性肿瘤和东部肿瘤协作组表现状态为0-2的患者符合条件。SCLC患者的初始队列(队列1)接受37-74MBq[89Zr]Zr-DFO-SC16.56作为单次静脉输注,总质量剂量为2·5mg,并在1小时进行了系列PET-CT扫描,注射后第1天,第3天和第7天。研究的第一阶段(队列1)的主要结果是估计终末间隙的一半时间,确定整个器官的时间整合活动系数,并评价[89Zr]Zr-DFO-SC16.56的安全性。其他患者的扩展队列(SCLC,神经内分泌前列腺癌,非典型类癌肿瘤,和非小细胞肺癌;队列2)以与初始队列相同的活性和质量剂量单次输注[89Zr]Zr-DFO-SC16.56,然后在3-6天后进行单次PET-CT扫描。通过免疫组织化学评估回顾性收集的肿瘤活检样品的DLL3。队列2研究的第2阶段的主要结果是确定示踪剂的肿瘤摄取与肿瘤内DLL3蛋白表达之间的潜在关联,通过免疫组织化学确定。这项研究正在进行中,并在ClinicalTrials.gov注册,NCT04199741。
结果:在2020年2月11日至2023年1月30日之间,有12名(67%)男性和6名(33%)女性入学,年龄中位数为64岁(范围23-81)。队列1包括3名患者,队列2包括15名其他患者。队列1中的三名SCLC患者的成像显示在注射后第3天和第7天强烈的肿瘤特异性吸收[89Zr]Zr-DFO-SC16.56。血清清除是双相的,估计的终末清除半衰期为119小时(SD31)。肝脏平均吸收剂量最高(1·83mGy/MBq[SD0·36]),平均有效剂量为0·49mSv/MBq(SD0·10)。在队列2中,给药后第3-6天的单次免疫PET-CT扫描可以描绘15名患者中12名(80%)的DLL3-狂热肿瘤。肿瘤摄取在患者之间和患者内部不同,在解剖部位,最大标准化吸收值范围很广(从3·3到66·7)。[89Zr]Zr-DFO-SC16.56的肿瘤摄取与DLL3免疫组织化学一致,在16例具有可评估组织的患者中,有15例(94%)。通过PET扫描,两名患有非恶性DLL3SCLC和神经内分泌前列腺癌的患者通过肿瘤免疫组织化学显示出最低的DLL3表达。18例患者中有1例(6%)出现1级过敏反应;两组均未出现2级或更严重的不良事件。
结论:DLL3PET-CT显像治疗神经内分泌癌是安全可行的。这些结果表明[89Zr]Zr-DFO-SC16.56用于非侵入性体内检测表达DLL3的恶性肿瘤的潜在用途。
背景:美国国立卫生研究院,前列腺癌基金会,和Scannell基金会.
BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer.
METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741.
RESULTS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort.
CONCLUSIONS: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies.
BACKGROUND: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.