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Background: The introduction of anti-PD-1 antibody has greatly improved the clinical outcomes of patients with lung cancer. Pre-treatment biomarkers in peripheral blood such as neutrophil-lymphocyte ratio, cytokine level, or clinical features such as BMI, lactate dehydrogenase, and prognostic nutrition index have been shown to be predictive markers treated by immunotherapy. Here we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced un-operable or metastatic lung cancer patients and report an association between peripheral blood biomarkers with clinical response in these patients. Methods: We conducted a single-center study by including medical record data for lung cancer patients treated with PD-1 antibody first-line or posterior-line either as monotherapy or in combination with chemotherapy. The patients enrolled from March 2020 to December 2021 were treated with albumin paclitaxel or pemetrexed plus carboplatin、lobaplatin or cisplatin combined with PD-1 antibody. The clinical response were assessed after 2 circles of therapy. Peripheral blood were drawn prior to therapy and post therapy. Multiple Th1 and Th2 cytokines levels in the blood serum were evaluated and phenotype of T cells of peripheral blood were also analyzed. The association between cytokines levels, T cells phenotype and clinical response were investigated. Results: 61 patients with stage IIIA-IV lung cancer were enrolled in the study. 40 non-squamous NSCLC patients, 15 Squamous NSCLC patients and 6 SCLC patients received PD-1 antibody with chemotherapy. 40(65.6%)patients were first-line therapy and 21(34.4%) were posterior-line treatment. 42(68.9%) patients achieved partial response(PR), 7 (11.5%) patients were stable(SD) and 12(19.6%) patients had progressed disease (PD). The disease control rare(DCR) was 80.4%. In DCR group, higher levels of IFN-γ(P = 0.023,P < 0.05), TNF-α(P = 0.007,P < 0.05)and IL-5 (P = 0.002, P < 0.005) were detected in peripheral blood prior to the treatment comparing to PD group. Besides, the reduction of lymphocyte absolute counts in peripheral blood after PD-1 antibody-based therapy was associated with disease progression(P = 0.023,P < 0.05). Furthermore, higher CD8⁺CD27⁺T cells in peripheral blood before therapy was associated with worse clinical response(P = 0.019,P < 0.05) and higher ratio of CD4⁺CD45RO⁺CD62L⁺/ CD4⁺CD45RO⁺CD62L^-seems to related with better clinical response, though without statistic difference due to limited sample size. Conclusions: These results suggest for the first time that serum IFN-γ, TNF-α and IL-5 levels could predict clinical efficacy with anti-PD-1 blockade therapy in lung cancer patients. Other biomarkers include lymphocyte counts or phenotype may also have predictive value. Large prospective studies need to further clarify the value of these biomarkers.

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背景：抗PD-1抗体的引入极大地改善了肺癌患者的临床结局。外周血中的预处理生物标志物，如中性粒细胞-淋巴细胞比率、细胞因子水平或临床特征，如 BMI、乳酸脱氢酶和预后营养指数，已被证明是免疫疗法治疗的预测标志物。在这里，我们回顾性分析了基于 PD-1 抗体的治疗对局部晚期不可手术或转移性肺癌患者的疗效，并报告了这些患者外周血生物标志物与临床反应之间的关联。方法：我们进行了一项单中心研究，纳入了接受 PD-1 抗体一线或后线治疗的肺癌患者的病历数据，无论是作为单一疗法还是与化疗相结合。2020年3月至2021年12月入组的患者接受白蛋白紫杉醇或培美曲塞联合卡铂、洛铂或顺铂联合PD-1抗体治疗。在 2 轮治疗后评估临床反应。在治疗前和治疗后抽取外周血。评估血清中多种 Th1 和 Th2 细胞因子水平，并分析外周血 T 细胞的表型。研究了细胞因子水平、T细胞表型和临床反应之间的关联。结果：61 名 IIIA-IV 期肺癌患者参加了该研究。40例非鳞状NSCLC患者、15例鳞状NSCLC患者和6例SCLC患者接受了PD-1抗体化疗。一线治疗40例（65.6%），后线治疗21例（34.4%）。42名（68.9%）患者达到部分缓解（PR），7名（11.5%）患者病情稳定（SD），12名（19.6%）患者出现疾病进展（PD）。疾病控制罕见（DCR）为80.4%。DCR组外周血中IFN-γ（P=0.023，P<0.05）、TNF-α（P=0.007，P<0.05）和IL-5（P=0.002，P<0.005）水平升高治疗前与 PD 组比较。此外，PD-1抗体治疗后外周血淋巴细胞绝对计数降低与疾病进展相关（P = 0.023，P < 0.05）。此外，更高的CD8⁺治疗前外周血中的CD27 ^{+ T 细胞与较差的临床反应相关（P = 0.019，P < 0.05）和较高的 CD4 +} CD45RO ⁺ CD62L ⁺ / CD4 ⁺ CD45RO ⁺ CD62L ^-似乎与更好的临床反应有关，尽管由于样本量有限而没有统计差异。结论：这些结果首次表明血清 IFN-γ、TNF-α 和 IL-5 水平可以预测肺癌患者抗 PD-1 阻断治疗的临床疗效。其他生物标志物包括淋巴细胞计数或表型也可能具有预测价值。大型前瞻性研究需要进一步阐明这些生物标志物的价值。