法国巴黎萨克雷大学Aurélien Marabelle小组的一项最新研究探明了肿瘤内抗CTLA4联合静脉抗PD1的安全性和有效性。相关论文于2026年4月29日发表于国际顶尖学术期刊《自然》杂志上。

在此，该课题组人员报告了随机多中心1b期NIVIPIT试验（ClinicalTrials.gov: NCT02857569），该试验招募了61例未经治疗的转移性黑色素瘤患者，随机分配2:1接受静脉注射nivolumab(抗PD1； 1mg/kg)联合单抗ipilimumab(抗CTLA4； 0.3mg/kg)或静脉注射伊匹单抗（抗CTLA4；3mg/kg）。主要终点达成：6个月时，瘤内注射组对比静脉注射组的3级或4级治疗相关不良事件发生率显著更低（22.6% vs 57.1%），与抗PD1单药治疗相当。根据RECIST（实体瘤疗效评价标准）评估的最佳客观缓解率，注射抗CTLA4的病灶达65.7%，未注射的病灶达50%，证实了瘤内暴露于抗CTLA4与疗效之间的关联。基线肿瘤免疫谱分析显示，促肿瘤的活化调节性T细胞和M2型巨噬细胞可预测持久临床获益，且与抗CTLA4给药途径无关。仅在获得持久临床获益的患者中观察到瘤内活化调节性T细胞的减少，这些患者还表现出高的瘤内Fcγ受体表达水平。本研究结果为寡转移及早期癌症采用瘤内抗CTLA4策略提供了理论依据，并提示高水平的瘤内活化调节性T细胞和FcγR⁺ M2型巨噬细胞是抗CTLA4联合抗PD1取得疗效的前提条件。

研究人员表示，静脉注射抗CTLA4和抗PD1提供了持久的肿瘤反应，但在癌症患者中会出现严重的治疗相关不良事件。以低剂量、高局部浓度给药可增强抗肿瘤效果，同时最大限度地减少全身暴露和毒性。

附：英文原文

Title: Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1

Author: Tselikas, Lambros, Susini, Sandrine, Texier, Matthieu, Yurchenko, Andrey, Routier, Emilie, Amini-Adle, Mona, Tihic, Edi, Mouraud, Sverine, Danlos, Franois-Xavier, Ammari, Samy, Raoult, Thibault, Roy, Sverine, Bredel, Delphine, Farhane, Siham, Cassard, Lydie, Molinaro, Irma, Eggermont, Alexander, Soria, Jean-Charles, Zitvogel, Laurence, Massard, Christophe, Paci, Angelo, de Baere, Thierry, Scoazec, Jean-Yves, Chaput, Nathalie, Nikolaev, Sergey, Meyer, Nicolas, Lebb, Cleste, Dalle, Stphane, Robert, Caroline, Marabelle, Aurlien

Issue&Volume: 2026-04-29

Abstract: Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer1. Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1mgkg1) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3mgkg1) or intravenous ipilimumab (3mgkg1). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (Treg) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural Treg cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fcγ receptor (FcγR) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated Treg cell and FcγR+ M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

DOI: 10.1038/s41586-026-10341-w

Source: https://www.nature.com/articles/s41586-026-10341-w