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Abstract：
Background: Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [177Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC. Methods: In this study, we evaluated the therapeutic and immunological action of [177Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [177Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [177Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling. Results: Biodistribution studies showed high tumor uptake of [177Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [177Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [177Lu]Lu-DOTA-hG250 + a-PD1. Ex vivo analyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment. Conclusions: Subtherapeutic [177Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.
摘要：
背景：免疫检查点抑制剂（ICI）通常用于晚期透明细胞肾细胞癌（ccRCC）。然而,大量患者对ICI治疗无反应.辐射是增加ICI应答率的有希望的方法,因为它可以产生抗肿瘤免疫。靶向放射性核素治疗(TRT)是一种全身放射治疗,非常适合转移癌症的精确照射。因此,本研究的目的是探索联合TRT的潜力，靶向在ccRCC中过表达的碳酸酐酶IX（CAIX），使用[177Lu]Lu-DOTA-hG250和ICI治疗ccRCC。方法:在本研究中,我们评估了[177Lu]Lu-DOTA-hG250联合aPD-1/a-CTLA-4ICI的治疗和免疫学作用。首先,在携带Renca-CAIX或CT26-CAIX肿瘤的BALB/cAnNRj小鼠中研究了[177Lu]Lu-DOTA-hG250的生物分布。Renca-CAIX和CT26-CAIX肿瘤的特征是T细胞浸润差和广泛的T细胞浸润，PD-L1表达同质和异质。分别。通过剂量学估计肿瘤吸收的辐射剂量。随后，[177Lu]通过监测肿瘤生长和存活来评估有和没有ICI的Lu-DOTA-hG250TRT功效。通过收集治疗前和治疗后5或8天的肿瘤组织来研究治疗诱导的肿瘤微环境变化，并通过免疫组织化学进行分析。流式细胞术,和RNA分析。结果:生物分布研究显示[177Lu]Lu-DOTA-hG250在两种肿瘤模型中的高肿瘤摄取。Renca-CAIX荷瘤小鼠的剂量递增治疗研究表明[177Lu]Lu-DOTA-hG250的剂量依赖性抗肿瘤功效和显着的治疗协同作用，包括假定的亚治疗TRT剂量时的完全缓解（4MBq，作为单一疗法没有明显疗效）与aPD-1+aCTLA-4联合使用。对于4MBq[177Lu]Lu-DOTA-hG250+a-PD1,在CT26-CAIX模型中获得了类似的结果。治疗肿瘤的离体分析显示DNA损伤，T细胞浸润,并调节联合治疗后TME中的免疫信号通路。结论：亚治疗[177Lu]Lu-DOTA-hG250联合ICI显示出更好的治疗效果，并显着改变了TME。我们的结果强调了在临床环境中对晚期ccRCC患者进行这种联合治疗的重要性。进一步的研究应集中在未来如何最佳地应用联合疗法。
