Introduction: Prostate cancer has been generally resistant to immunotherapy approaches. Radiation can be immunostimulatory, but the extent to which standard prostate cancer treatments induce immune activation has not been well described. The bone-targeted radiopharmaceutical Radium223 (Ra223) has been proposed to enrich immune function, but clinical studies have not fully delineated whether this is true, or by what mechanisms. Enzalutamide has been shown to increase PD-L1 expression on dendritic cells, which could impact immune activation, though the extent to which this is associated with other evidence of immune activation remains uncertain, and combination strategies remain of interest. We performed a randomized phase II trial to evaluate whether Radium223 (Ra223) added to enzalutamide would induce greater immune activation and clinical responses compared to enzalutamide alone in men with metastatic castration-resistant prostate cancer (mCRPC). Methods: Eligible patients were randomized 2:1 to Arm A (enzalutamide 160 mg PO daily + Ra223 55 kBq/kg IV q4 weeks × 6 doses) or Arm B (enzalutamide 160 mg PO daily). Blood was collected at treatment start and during treatment to measure soluble immune checkpoint biomarkers (BTLA, TIM3, HVEM, GITR, LAG3, PD-1, CTLA-4, PD-L1, PD-L2, ICOS). Immunophenotyping by mass cytometry time of flight (CyTOF) was performed to measure peripheral blood mononuclear cell populations before and after treatment. CyTOF was used to determine changes in circulating immune cell population subsets before and after treatment. Biopsies were performed of an active bone metastatic lesion prior to study treatment and after at least 3 months. IHC was subsequently performed to examine changes in immune cell population subsets before and after treatment, and changes in pSTAT3 levels. Results: In total, 30 patients were enrolled, with median age 68. The median duration of follow up was 36 months. PSA responses, PFS, and OS were not significantly different between the two arms; however, the study was not powered for clinical endpoints. Peripheral blood and bone biopsy specimens were analyzed for immune correlatives. Soluble receptor concentrations showed significantly increased expression of PDL-2 in the combination arm, but this was not seen on CyTOF. Otherwise, there were no significant differences in markers of immune activation/exhaustion or immune cell population subsets in the combination arm and enzalutamide monotherapy arm. IHC also did not show a significant difference in immune cell population subsets in bone biopsy specimens before and after treatment in both arms. However, treatment with the combination arm did show significantly increased levels of pSTAT3 (p= 0.04), which was not seen in the enzalutamide monotherapy arm. Conclusions: Our study showed an overall lack of evidence for immune activation or cytokine induction with the combination, which does not make a strong case for combinatorial immunotherapy approaches. However, the combination did induce higher levels of pSTAT3, which has been implicated in radio-resistance. Therefore, the addition of a STAT3 inhibitor to the combination may be of interest to improve efficacy.
引言：前列腺癌通常对免疫疗法具有抵抗性。放射治疗可产生免疫刺激作用，但标准前列腺癌治疗在多大程度上能诱导免疫激活尚未得到充分阐述。骨靶向放射性药物镭223（Ra223）被认为可能增强免疫功能，但临床研究尚未完全阐明其真实性及作用机制。恩杂鲁胺已被证实能增加树突状细胞上的PD-L1表达，这可能影响免疫激活，但其与其他免疫激活证据的关联程度仍不明确，联合治疗方案仍值得关注。我们开展了一项随机II期临床试验，旨在评估在转移性去势抵抗性前列腺癌（mCRPC）患者中，相较于恩杂鲁胺单药治疗，联合使用镭223（Ra223）是否能诱导更强的免疫激活和临床应答。 方法：符合入组条件的患者按2:1比例随机分配至A组（恩杂鲁胺160mg每日口服+Ra223 55 kBq/kg每4周静脉给药×6次）或B组（恩杂鲁胺160mg每日口服）。在治疗开始及治疗期间采集血液样本，检测可溶性免疫检查点生物标志物（BTLA、TIM3、HVEM、GITR、LAG3、PD-1、CTLA-4、PD-L1、PD-L2、ICOS）。采用飞行时间质谱流式细胞术（CyTOF）进行免疫表型分析，测定治疗前后外周血单个核细胞群。通过CyTOF分析治疗前后循环免疫细胞亚群的变化。在治疗前及治疗至少3个月后，对活动性骨转移病灶进行活检。随后通过免疫组化检测治疗前后免疫细胞亚群及pSTAT3水平的变化。 结果：共纳入30例患者，中位年龄68岁。中位随访时间为36个月。两组间PSA应答率、无进展生存期和总生存期均无显著差异；但本研究未针对临床终点进行效能检验。对两组患者的外周血和骨活检样本进行免疫相关性分析。可溶性受体浓度检测显示联合治疗组PD-L2表达显著升高，但CyTOF分析未观察到该现象。此外，联合治疗组与恩杂鲁胺单药组在免疫激活/耗竭标志物或免疫细胞亚群方面均无显著差异。免疫组化分析亦显示两组患者骨活检样本治疗前后的免疫细胞亚群均无显著差异。然而，联合治疗组确实显示出pSTAT3水平显著升高（p=0.04），而恩杂鲁胺单药组未见此现象。 结论：本研究总体缺乏联合治疗方案能激活免疫或诱导细胞因子的证据，这未能为联合免疫疗法提供有力支持。但联合治疗确实诱导了更高水平的pSTAT3，而该因子与放射抵抗性相关。因此，在联合方案中添加STAT3抑制剂可能有助于提高疗效。
肿瘤(癌症)患者之家