PO.ET08.01 · 实验与分子治疗
在LNCaP前列腺癌异种移植模型中对68Ga-PSMA、177Lu-PSMA治疗以及生物标志物指导的免疫治疗和DDR抑制剂联合方案的诊疗一体化评估
Theranostic evaluation of 68 Ga-PMSA, 177 Lu PSMA therapy, and biomarker guided immunotherapy and DDR inhibitor combinations in LNCaP prostate cancer xenografts
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摘要 Abstract
中文摘要
背景与理论依据。以177Lu-PSMA进行的PSMA靶向放射性配体治疗是转移性去势抵抗性前列腺癌一种有前景的治疗方法。为优化其临床转化，需要临床前模型将诊断成像与剂量学联系起来、评估应答生物标志物并评估增敏性联合方案。我们使用LNCaP异种移植模型开展了一项体内研究，比较177Lu-PSMA单药治疗与免疫治疗、DDR抑制及其联合方案，整合了多模态成像、药代动力学、毒性和离体生物标志物分析。
方法。荷LNCaP肿瘤（100-150 mm³）的雄性免疫缺陷小鼠接受基线18F-PSMA PET/CT以确认摄取和病灶剂量学，随后随机分为6个队列（n=8-10）。1. 载体对照；2. 177Lu-PSMA单药治疗（最小有效剂量）；3. 抗PD-1；4. 177Lu联合抗PD-1；5. 177Lu联合PARP抑制剂；6. 三联联合。在第7、14和28天进行纵向18F-PSMA成像以监测早期代谢应答，同时监测肿瘤体积和体重。177Lu给药后（1-96小时）采集血样以了解PK和清除情况，并同时进行血常规（CBC）和血清生化检查以评估全身毒性。终点时收获肿瘤进行免疫染色和分子分析，检测增殖、免疫应答和DDR抑制的标志物。此外，还评估了PBMC中的探索性gammaH2AX和ctDNA分析作为转化生物标志物。
结果。18F-PSMA-PET早期摄取和诊断评估与177Lu疗效相关。最小剂量177Lu维持了显著的抗肿瘤活性并降低了血液学毒性。与抗PD-1联合通过放射增敏增强了疗效。三联治疗产生了最大的肿瘤抑制且毒性可控。离体生物标志物为各队列提供了机制性见解和预测性关联。
结论。这项整合的临床前研究表明，177Lu-PSMA的效率可通过免疫治疗和DDR抑制得到增强。多模态成像、PK、毒性和生物标志物分析为未来前列腺癌临床试验的合理给药、联合设计和转化策略提供了依据。
查看英文原文 English abstract
Background and Rationale. PSMA-targeted radioligand therapy with 177 Lu-PMSA is a promising treatment for metastatic castration-resistant prostate cancer. To optimise its clinical translation, preclinical models are required to link to diagnostic imaging with dosimetry, assess biomarkers or response, and evaluate sensitising combination. We conducted an in vivo study using LNCaP xenograft model comparing 177 Lu-PSMA monotherapy with immunotherapy, DDR inhibition and combinations, integrating multimodal imaging, pharmacokinetics, toxicity, and ex vivo biomarker analyses.
Methods. Male immunodeficient mice bearing LNCaP tumours (100-150mm 3 ) underwent baseline 18 F-PSMA PET/CT to confirm uptake and lesion dosimetry, then were randomised into 6 cohorts (n 8-10). 1. Vehicle; 2. 177 Lu-PSMA monotherapy (minimal effective dose); 3. anti-PD-1; 4. 177 Lu plus anti-PD-1; 5. 177 Lu plus PARP inhibitor, 6. Triple combination. Longitudinal 18 F-PSMA at 7, 14, and 28 days monitored early metabolic response, alongside tumour volume and body weight. Blood samples post 177 Lu (1-96 h) informed PK and clearance, with concurrent CBC and serum chemistry to assess systemic toxicity. At endpoint, tumours were harvested for immunostaining and molecular analysis for markers of proliferation, immune response and DDR inhibition. In addition, exploratory gammaH2AX in PBMCs and ctDNA profiling were assessed as translational biomarkers.
Results. 18 F-PSMA-PET early uptake and diagnostic assessment correlated with 177 Lu efficacy. Minimal dose 177 Lu maintained significant anti-tumour activity and reduced haematologic toxicity. Combination with anti-PD-1 enhanced efficacy via radio sensitisation. Triple therapy produced maximal tumour suppression with manageable toxicity. Ex vivo biomarkers provided mechanistic insight and predictive correlates across cohorts.
Conclusions. This integrated preclinical study demonstrates that 177 Lu-PSMA efficiency is enhanced by immunotherapy and DDR inhibition. Multimodal imaging, PK, toxicity, and biomarker analyses inform rational dosing, combination design, and translational strategies for future clinical trials in prostate cancer.
利益披露 Disclosure
J. Maynard, None..
A. Liu, None..
B. Arno, None..
T. Hall, None..
W. Drewe, None..
K. Shea, None..
A. Rutkowski, None..
G. Haydon, None..
T. Allen, None..
F. Yau, None..
L. Lucaciu, None..
M. Griffiths, None..
G. Marshall, None.