PO.CL01.09 · 临床研究
使用靶向α发射体212Pb-DOTAMTATE AlphaMedix治疗的转移性神经内分泌肿瘤（NET）患者的动态全身免疫调节
Dynamic systemic immune modulation in metastatic neuroendocrine tumor (NET) patients treated with targeted alpha-emitter 212 Pb-DOTAMTATE AlphaMedix
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肽受体放射性核素治疗（PRRT）作为多种实体瘤（如前列腺癌和表达生长抑素受体的GEP-NET）的治疗策略已日益受到探索。Lutathera（¹⁷⁷Lu-DOTATATE）是一种β发射的PRRT，代表当前GEP-NET的标准治疗。而α发射的PRRT，如AlphaMedix（²¹²Pb-DOTAMTATE），凭借其独特的放射生物学特性正成为有前景的替代方案。PRRT产生的电离辐射不仅诱导DNA损伤，还调节免疫系统，从而促成治疗反应。我们试图寻找与α发射体AlphaMedix治疗相关的全身免疫调节的证据，并将其与Lutathera所引发的免疫调节进行比较。使用LITOSeek平台分析全血免疫转录组，以表征α发射和β发射PRRT差异激活的免疫特征和通路。该方法阐明了α粒子治疗背后的免疫学机制，并揭示了治疗反应的潜在生物标志物。
方法：使用PAXgene Blood RNA管从GEP-NET患者在AlphaMedix或Lutathera治疗前及整个治疗过程中采集全血样本。采用差异表达、过表征分析、数字细胞计数和轨迹识别来表征治疗诱导的外周免疫转录组、免疫细胞组成的调节以及患者群体内的异质性反应。
结果：AlphaMedix治疗在获得完全或部分反应的患者中诱导了强烈的外周转录组变化，从首次输注后8周开始可检测到，并持续至治疗结束后6个月。AlphaMedix在对治疗有反应的患者中引发相似的转录组变化，这些变化比接受Lutathera治疗的患者更强且不同。212Pb放射配体治疗引发ROS的早期生成、DNA损伤、凋亡反应、炎症和单核细胞募集。结果揭示了两波免疫转录组调节，可能反映了早期和晚期反应者之间免疫激活的动力学异质性。在接受AlphaMedix或Lutathera治疗的患者中均观察到淋巴细胞减少，尤其影响B细胞，接受Lutathera治疗的患者中淋巴细胞减少更为明显。
结论：对外周免疫细胞中治疗相关转录变化的数据驱动表征，凸显了与放射配体治疗临床反应相关的免疫调节。通过对患者放射配体治疗反应的免疫药效学分析以及免疫相关临床反应生物标志物的识别，证明了全血RNA液体活检的转化潜力。
查看英文原文 English abstract
Peptide receptor radionuclide therapy (PRRT) has been increasingly explored as a therapeutic strategy for multiple solid tumors, such as prostate cancer and somatostatin receptor-expressing GEP-NETs. While Lutathera (¹⁷⁷Lu-DOTATATE), a beta-emitting PRRT, represents the current GEP-NETs standard of care. alpha-emitting PRRTs such as AlphaMedix (²¹²Pb-DOTAMTATE) are emerging as promising alternatives with distinct radiobiological characteristics. Ionizing radiation from PRRT not only induces DNA damage but also modulate the immune system, contributing to therapeutic response.We sought to identify evidence of systemic immunomodulation associated with alpha-emitter AlphaMedix treatment and to compare it with that elicited by Lutathera. Whole-blood immunotranscriptomes were analyzed using the LITOSeek platform to characterize immune signatures and pathways differentially activated by alpha- and beta-emitting PRRTs. This approach elucidates the immunological mechanisms underlying alpha-particle therapy and uncovers potential biomarkers of treatment response.
Methods: Whole blood samples were collected with PAXgene Blood RNA tubes from GEP-NET patients before and throughout AlphaMedix or Lutathera treatment. Differential expression, over-representation analysis, digital cytometry, and trajectory identification were used to characterize treatment-induced regulation of peripheral immunotranscriptomes, immune cell composition, and heterogenous responses within the patient population.
Results: AlphaMedix therapy induced strong peripheral transcriptomic changes in patients achieving complete or partial response, detectable from 8 weeks after first infusion, and up to 6 months after end of treatment. AlphaMedix triggers similar transcriptomic changes throughout the treatment among patients responding to the therapy, which is stronger and different from patients treated with Lutathera. The 212 Pb radioligand therapy triggers early generation of ROS, DNA damage, apoptotic responses, inflammation and monocyte recruitment. The results reveal two waves of immunotranscriptome modulation, likely reflecting kinetics heterogeneity of immune activation between early and late responders. Lymphopenia, particularly affecting B cells, was observed in patients treated with either AlphaMedix or Luthatera, with more pronounced lymphopenia among patients treated with Lutathera.
Conclusions: Data-driven characterization of treatment-associated transcriptional changes in peripheral immune cells underscores immune modulation associated with clinical response to radioligand therapy. The translational potential of whole-blood RNA liquid biopsy is demonstrated with Immuno-Pharmacodynamic profiling of patient response to radioligand therapy, and identification of immune-related biomarkers of clinical response.
利益披露 Disclosure
A. J. Conforte,
Novigenix SA Employment, Stock Option.
I. Tworowska,
RadioMedix Employment, g., Board of Directors, non-salaried role).
S. F. Costa,
Novigenix SA Employment.
M. Brzezinska,
Novigenix SA Employment, Stock Option.
A. M. Usatorres,
Novigenix SA Employment, Stock Option.
N. Hadadi,
Novigenix SA Employment, Stock Option.
S. Monnier-Benoit,
Novigenix SA Employment, Stock, Stock Option, Patent.
S. Pavan,
Novigenix SA Employment, Stock Option.
R. Esfandiari, None.
B. Hashemi,
Novigenix SA Employment, g., Board of Directors, non-salaried role), Stock, Stock Option.
P. Romero,
Novigenix SA Employment, g., Board of Directors, non-salaried role), Stock Option.
E. S. Delpassand,
RadioMedix Employment, g., Board of Directors, non-salaried role).