Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PRLT) with Lutetium-177 ([177Lu]Lu-PSMA) is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The aim of our study was to evaluate clinical variables of patients with extreme response to PRLT and to assess its immunomodulatory potential. Methods: This retrospective study included 36 patients from two centers achieving extreme response after [¹⁷⁷Lu]Lu-PSMA PRLT. The primary outcomes were the duration of maintained response in months (MR) and improvement post-therapy—clinically, serologically, and on molecular (PET/CT) imaging. We examined several variables, including pathology, gene sequencing, baseline PSA, Gleason score, prior therapies, number of PRLT cycles, and pattern of disease, to identify potential factors that may influence the extreme response. Results: Between 2018 and mid-September 2024, 36 men with mCRPC received a mean of three cycles of [177Lu]Lu-PSMA PRLT. Patients were subgrouped according to clinical variables versus MR. A total of 17 patients had ≥12 months MR (17/36, 47%). The longest duration of MR was 99 months and a mean of 17.44 months (95% CI 10.05–24.84). Previous lines of treatment were evaluated for MR,p= 0.172. Pattern of disease (bone, lymph node, liver, and peritoneal) was evaluated for MR,p= 0.721. The Gleason score was evaluated for MR,p= 0.871. Patients with known BRCA sequencing status (n = 12) were analyzed with mean MR: BRCA1/2 wild-type, 6/12 (50%), 6.67 months; BRCA 1/2 negative, 1/12 (8.33%), 7 months; BRCA germline negative and somatic positive, 1/12 (8.33%), 36 months; BRCA germline negative, somatic negative, 2/12 (16.67%), 27 months; and BRCA 2 positive, 2/12 (16.67%), 43 months. Conclusions: We propose there may be intrinsic mechanisms suggesting the immunomodulatory enhancement of ionizing radiation, primarily driving extreme responses.
背景：针对前列腺特异性膜抗原（PSMA）的放射性配体疗法（PRLT），特别是使用镥-177标记的PSMA抑制剂（[¹⁷⁷Lu]Lu-PSMA），是治疗转移性去势抵抗性前列腺癌（mCRPC）的一种安全有效的方法。本研究旨在评估对PRLT产生极端反应患者的临床变量，并探讨其潜在的免疫调节作用。方法：这项回顾性研究纳入了来自两个中心的36例在接受[¹⁷⁷Lu]Lu-PSMA PRLT后达到极端反应的患者。主要结局指标为维持反应的持续时间（以月计，MR）以及治疗后临床、血清学和分子影像学（PET/CT）上的改善。我们分析了多项变量，包括病理学特征、基因测序结果、基线前列腺特异性抗原（PSA）水平、格里森评分、既往治疗史、PRLT周期数以及疾病分布模式，以识别可能影响极端反应的潜在因素。结果：在2018年至2024年9月中旬期间，36例mCRPC男性患者平均接受了三个周期的[¹⁷⁷Lu]Lu-PSMA PRLT。根据临床变量与维持反应时间对患者进行亚组分析。共有17例患者维持反应时间≥12个月（17/36，47%）。最长的维持反应时间为99个月，平均为17.44个月（95% CI 10.05–24.84）。评估既往治疗线数对维持反应时间的影响，p=0.172。评估疾病分布模式（骨、淋巴结、肝脏、腹膜）对维持反应时间的影响，p=0.721。评估格里森评分对维持反应时间的影响，p=0.871。对已知BRCA测序状态的患者（n=12）进行分析，其平均维持反应时间为：BRCA1/2野生型，6/12（50%），6.67个月；BRCA 1/2阴性，1/12（8.33%），7个月；BRCA胚系阴性且体细胞阳性，1/12（8.33%），36个月；BRCA胚系阴性，体细胞阴性，2/12（16.67%），27个月；BRCA 2阳性，2/12（16.67%），43个月。结论：我们认为可能存在内在机制，提示电离辐射的免疫调节增强作用可能是驱动极端反应的主要因素。
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