背景:免疫检查点抑制剂联合化疗作为新辅助疗法已应用于食管鳞状细胞癌(ESCC)的治疗。然而,最佳方案需要进一步探索,特别是对于老年患者,免疫检查点抑制剂联合化疗调节ESCC演变的机制尚不清楚。
方法:在这项单臂2期试验中,入组可切除(II/III/IV期无转移)ESCC患者,接受纳米颗粒白蛋白结合(nab)紫杉醇治疗2个周期,口服S-1治疗2周,术前联合静脉注射托利帕利马两个周期。给予联合术后辅助治疗。主要结果是主要病理反应(MPR)。次要结果包括病理完全缓解(pCR),总反应率(ORR),疾病控制率(DCR),无病生存率(DFS),总生存期(OS),改善Stooler吞咽困难评分和日常生活能力(dADL)。使用全外显子组测序进行新辅助治疗前后的活检和血浆,转录组测序,PD-L1的免疫组织化学(IHC),多重免疫荧光(mIF)和92种蛋白质的邻近延伸测定技术(PEA)。
结果:从2019年11月至2021年7月,60名患者被纳入研究。新辅助治疗后,55例(98.21%)患者实现了R0切除。在27例患者中发现MPR(49.09%),16例(29.09%)患者达到pCR。PR患者,SD和PD分别为37(61.67%),21(35.00%)和2(3.33%),分别。整体分期,治疗后Stooler吞咽困难评分和dADL明显下降。11例患者(18.3%)出现≥3级AE。与PD-L1低患者相比,PD-L1-High患者的PR比率明显更高。在治疗期间,PR患者的肿瘤突变负荷(TMB)和肿瘤新抗原负荷(TNB)显著降低.肿瘤内异质性的分析证明了肿瘤内的差异克隆进化。转录组分析显示,基线时CD4+T淋巴细胞浸润与临床结果相关。在治疗期间,所有患者的CD8+T细胞和CD4+T细胞均增加;然而,耗尽的细胞,nTregs和iTregs在非MPR患者中显著增加。蛋白质分析显示,IFN-γ的水平,Gal.1和LAMP3可以预测临床获益。此外,CD83、TNFRSF4、TNFSF14、VEGFR2、ADA、ARG1和HO-1与严重AE相关。更重要的是,CD4+T细胞与IFN-γ血浆蛋白的整合,Gal.1或LAMP3可以进一步区分应答者和非应答者。
结论:在这项研究中,托里帕利单抗的新辅助治疗,nab-紫杉醇和S-1在可切除的ESCC患者中毒性较小,并显示出有希望的抗肿瘤活性。基因组的变化,转录组,对PD-L1表达和血清蛋白进行综合分析,并与临床结局相关,这有助于深入了解toripalimab联合nab-紫杉醇和S-1在ESCC患者中的作用机制。
背景:本研究由国家科技部“十三五”重大项目资助[资助号:2018ZX09201013]。
BACKGROUND: Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown.
METHODS: In this single-arm phase 2
trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler\'s dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins.
RESULTS: From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders.
CONCLUSIONS: In this
study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC.
BACKGROUND: This
study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].