PDF(Pubmed)
Abstract：
Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.
摘要：
通过将外部束放射疗法（EBRT）和前列腺特异性膜抗原（PSMA）靶向的放射性配体疗法（RLT）与lute-177（177Lu）标记的PSMA抑制剂相结合，可以改善前列腺癌（PC）的管理。我们假设，由于肿瘤的放射剂量增加以及EBRT与PSMA表达的相互作用可能会增加放射性药物的摄取，因此该组合的疗效更高。因此,本研究分析了辐射对PSMA表达水平的影响。翻译结果以评估光子EBRT和[177Lu]Lu-PSMA-617的组合在鼠PC异种移植模型中的功效。最后,关于选择性视野EBRT和RLT剂量递增的临床病例报告说明了概念验证。方法：使用逆转录定量聚合酶链反应（RT-qPCR）评估辐射后过表达人PSMA的LNCaP细胞中PSMA基因和蛋白质的表达，流式细胞术和On-CellWestern分析。在体内治疗研究中，将LNCaP荷瘤BALB/cnu/nu小鼠用2GyX射线EBRT照射一次，并在4小时后注射40MBq[177Lu]Lu-PSMA-617或接受单一或不治疗（每个n=10）。[177Lu]Lu-PSMA-617的肿瘤吸收剂量是在使用伽马探针得出时间-活性曲线后，根据医学内部放射剂量测定（MIRD）形式计算的。证实了一个示例性患者病例，其中分段EBRT（前列腺54Gy；骨盆淋巴管45Gy）和[177Lu]Lu-PSMA-617的三个周期（每个周期3.4-6.0GBq）在并发雄激素剥夺下依次组合用于治疗局部晚期PC。结果：在2-8Gy照射后4小时，LNCaP细胞显示PSMA蛋白上调约18％，相对于未照射的细胞，和mRNA水平上更强的上调（高达2.6倍）。当PSMA蛋白水平下调高达22％时，这种作用在24小时内逆转。与单次或无治疗相比,用联合治疗治疗的小鼠显示出关于肿瘤控制和中位存活(p<0.0001)的显著改善的结果。相对于PSMA-RLT或EBRT的单一疗法，肿瘤倍增时间延长1.7倍或2.7倍，中位生存期延长24%或60%，分别。此外,用EBRT治疗的肿瘤显示放射性药物的摄取增加了14％，从计算的肿瘤吸收剂量可以明显看出，尽管数据有很高的可变性。关于病人的情况，三联疗法的耐受性良好,PSMA-RLT治疗结束后,患者在5年内获得了持久的生化完全缓解.然后，患者在随访成像中出现了生化复发，并伴有寡复发性疾病。结论：目前的临床前和临床数据表明，EBRT与PSMA-RLT剂量递增的组合可以改善肿瘤控制并可能延长生存期。这可能为这种方法的进一步临床研究铺平道路，以探索联合疗法的治愈潜力。
