PRRT联合PD-1/PD-L1单抗治疗SSTR表达阳性的胰腺神经内分泌肿瘤的研究

Currently, the treatment with peptide receptor radionuclide therapy (PRRT) targeting somatostatin receptor (SSTR) resulted in high efficacy and safety for pancreatic neuroendocrine neoplasms (pNENs) expressing SSTR. However, some patients still have no treatment response or even progressive disease. On the one hand, PRRT had short-term and long-term side effects and the accumulated doses needed to be controlled. On the other hand, some well-differentiated pNENs may change the differentiation degree during proliferation, metastasis or recurrence due to the heterogeneity of pNENs, thus affecting the efficacy of PRRT..PD-1/PD-L1 is an immune checkpoint pathway and anti-PD-1/PD-L1 monoclonal antibodies are novel immunotherapies for cancer, but the efficacy of anti-PD-1/PD-L1 monoclonal antibodies alone for pNENs is limited. Several studies have shown that radiotherapy combined with anti-PD-1/PD-L1 monoclonal antibodies can improve the efficacy of tumor treatment. PRRT has a similar biological effect and better targeting than radiotherapy and can induce the up-regulation of PD-L1 expression of tumor cells and tumor-infiltrating immune cells, and accumulate more tumor-infiltrating immune cells in tumor microenvironment. Therefore, it is speculated that PRRT combined with anti-PD-1/PD-L1 monoclonal antibody has a synergistic antitumor effect on the treatment of pNENs expressing SSTR..This project intends to study the efficacy of PRRT combined with the anti-PD-1/PD-L1 monoclonal antibody in the treatment of pNENs expressing SSTR at the cellular and in vivo levels, and explore the appropriate treatment dose of PRRT and the best opportunity for combined treatment. The purpose of this study is to provide a guideline for the further clinical transformation of PRRT combined with immunotherapy.

目前靶向生长抑素受体（SSTR）的肽受体放射性核素治疗（PRRT）对于SSTR表达阳性的胰腺神经内分泌肿瘤（pNENs）获得了较高的治疗反应率和安全性，但仍有部分患者无应答甚至进展。已有研究证实放疗联合PD-1/PD-L1单抗能提高肿瘤疗效，PRRT具有与放疗相似的生物学效应和更好的靶向性，故推测对于SSTR表达阳性的pNENs，PRRT能够诱导肿瘤细胞和肿瘤浸润性免疫细胞PD-L1的表达上调，在肿瘤微环境中募集更多的免疫细胞，从而与PD-1/PD-L1单抗治疗有协同作用。本项目拟从细胞和动物水平观察PRRT治疗后肿瘤细胞和肿瘤浸润性免疫细胞PD-L1表达的改变，以及PRRT联合PD-1/PD-L1单抗的疗效，探索适宜的PRRT剂量及联合治疗的最佳时机，为PRRT联合PD-1/PD-L1单抗治疗提供数据支持，为进一步提高pNENs的疗效提供新途径。

背景：177Lu靶向生长抑素受体（SSTR）已经在临床前及临床研究中取得了良好的安全性及疗效。已有研究证实放疗联合PD-1/PD-L1单抗有协同效应，而177Lu靶向SSTR治疗联合PD-1/PD-L1单抗治疗的安全性和疗效尚缺乏充足的理论及数据支持。本项目旨在从细胞和动物水平探索177Lu靶向SSTR治疗联合PD-1/PD-L1单抗治疗的安全性、疗效及协同效应机制。.研究内容：从离体细胞实验证实mc38-SSTR2及B16F10-SSTR2细胞在177Lu-DOTA-JR11孵育后不同时间点PD-L1的表达；从动物水平验证177Lu-DOTA-JR11联合PD-L1单抗治疗的安全性和疗效；构建B16F10-SSTR2/B16F10-widetype异质性双瘤小鼠模型，验证177Lu-DOTA-JR11联合PD-L1单抗治疗的“远隔效应”。.重要结果及关键数据：离体细胞实验证实177Lu-DOTA-JR11孵育后0h、1d的PD-L1水平明显升高，之后逐渐减低；177Lu-DOTA-JR11联合PD-L1单抗治疗有较好的安全性和疗效，联合治疗组肿瘤组织的ki67明显减低，CD8、CD45、Granzyme B表达明显升高；B16F10-SSTR2/B16F10-widetype异质性双瘤小鼠模型中，联合治疗组不仅对高表达SSTR2肿瘤有抑制作用，对无明显SSTR2表达的野生肿瘤也有抑制作用。.科学意义：177Lu靶向核素治疗联合PD-1/PD-L1单抗有良好的安全性和疗效，且对于异质性较高的神经内分泌肿瘤，两者的联合具有“远隔效应”。这一结果对于异质性较高的神经内分泌肿瘤的临床治疗策略具有重要的意义，也为更多的靶向核素治疗联合PD-1/PD-L1单抗治疗的临床研究提供了理论依据和数据支持。