Xiang Xiaosong, Guo Feilong, Li Guoli, Ma Long, Zhu Xi, Abdulla Zulpikar, Li Jiafei, Zhang Junling, Huang Mengli
Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Department of Biostatistics, Columbia University, New York, NY, United States.
Front Oncol. 2023 Jan 5;12:1015962. doi: 10.3389/fonc.2022.1015962. eCollection 2022.
The prognosis of unresectable gastric cancer is poor, while the efficacy of anti-PD antibodies has not been evaluated.
Patients with unresectable gastric cancer who received intra-arterial chemotherapy (IAC) with sequential anti-PD-1 antibody as induction therapy in Jinling Hospital were retrospectively analyzed. The primary outcome is R0 resection rate. The secondary outcomes include safety, conversion surgery rate, overall survival (OS) and progression free survival (PFS) after postoperative IAC and anti-PD-1 treatments. Meanwhile, Tumor immunity in the microenvironment (TIME) before and after IAC was comprehensively dissected with multiplex immunofluorescence in order to detect possible mechanisms favoring anti-PD-1 treatment response.
Between May 2019 and October 2020, 36 patients received at least one cycle of IAC with sequential anti-PD-1 antibody in our institution. The objective response was achieved in 28 patients (77.8%). Thirty patients (83.3%) successfully underwent conversion surgery, among which R0 resection was managed in 25/30 patients, and 23.3% (7/30) was assessed as pathological complete remission. During the median follow-up period of 19.7 months, patients who underwent R0 resection displayed superior OS (HR 0.14 [95% CI 0.04-0.50], P < 0.0001) and PFS (HR 0.11 [0.03-0.44], P < 0.0001) than those who did not. Grade 3 adverse events (AEs) were only encountered in 19.4% patients, no grade 4 AEs observed. In TIME analysis, the number of tertiary lymphoid structures (TLSs) (P = 0.004) were greatly induced by IAC, as well as CD8 T cells (P = 0.011) and PD-1 cells (P = 0.025). Meanwhile, Tumor associated macrophages shifted towards anti-tumor M1-like subtypes, with CD68CD163 M2-like subpopulation significantly decreased (P = 0.04).
Preoperative IAC with sequential anti-PD-1 antibody exhibited promising clinical benefit for unresectable gastric cancer with remarkable conversion rate and R0 resection rate, and also prolonged survival as postoperative regimen. TIME transformation induced by ICA might mediate the additive effect with the immune checkpoint inhibitor.
不可切除胃癌的预后较差，而抗程序性死亡（PD）抗体的疗效尚未得到评估。
对在金陵医院接受动脉内化疗（IAC）联合序贯抗PD-1抗体作为诱导治疗的不可切除胃癌患者进行回顾性分析。主要结局是R0切除率。次要结局包括安全性、转化手术率、术后IAC和抗PD-1治疗后的总生存期（OS）和无进展生存期（PFS）。同时，采用多重免疫荧光技术全面剖析IAC前后肿瘤微环境（TIME）中的肿瘤免疫情况，以探寻有利于抗PD-1治疗反应的可能机制。
2019年5月至2020年10月期间，我院36例患者接受了至少一个周期的IAC联合序贯抗PD-1抗体治疗。28例患者（77.8%）获得客观缓解。30例患者（83.3%）成功接受了转化手术，其中25/30例患者实现了R0切除，23.3%（7/30）的患者被评估为病理完全缓解。在19.7个月的中位随访期内，接受R0切除的患者的OS（风险比[HR]0.14[95%置信区间（CI）0.04 - 0.50]，P < 0.0001）和PFS（HR 0.11[0.03 - 0.44]，P < 0.0001）均优于未接受R0切除的患者。仅19.4%的患者出现3级不良事件（AE），未观察到4级AE。在TIME分析中，IAC显著诱导了三级淋巴结构（TLSs）的数量（P = 0.004）、CD8 T细胞数量（P = 0.011）和PD-1细胞数量（P = 0.025）。同时，肿瘤相关巨噬细胞向抗肿瘤的M1样亚型转变，CD68⁺CD163⁺ M2样亚群显著减少（P = 0.04）。
术前IAC联合序贯抗PD-1抗体对不可切除胃癌显示出有前景的临床获益，具有显著的转化率和R0切除率，并且作为术后治疗方案还延长了生存期。IAC诱导的TIME转变可能介导了与免疫检查点抑制剂的相加作用。
