Microbiology and Immunology PhD Program, University of Zurich, Zurich, Switzerland.
Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland.
JAMA Oncol. 2019 Jul 1;5(7):1043-1047. doi: 10.1001/jamaoncol.2019.0402.
Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy.
To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer.
DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year.
Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations).
Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy.
These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.
针对 PD-1（程序性细胞死亡 1）轴的检查点抑制剂的免疫疗法在非小细胞肺癌（NSCLC）和其他癌症患者中带来了显著的进展。然而，自身免疫毒性作用频繁且尚未得到充分理解，因此了解检查点抑制剂治疗引起的自身免疫不良反应的病理生理过程非常重要。
深入了解抗 PD-1 治疗引起的非小细胞肺癌患者的皮肤自身免疫毒性作用的机制。
设计、地点和参与者：这项前瞻性队列研究于 2016 年 7 月 1 日至 2018 年 12 月 31 日进行。从瑞士的 4 个不同中心（Kantonsspital St Gallen、Spital Grabs、Spital Wil 和 Spital Flawil）招募了接受抗 PD-1 治疗（nivolumab 或 pembrolizumab）的非小细胞肺癌患者（n=73）。在 2 年期间采集外周血单核细胞、肿瘤活检标本和自身免疫性皮肤毒性作用部位的活检标本，在 1 年后对患者进行随访。
治疗反应、总生存期、无进展生存期和自身免疫毒性作用的发生（基于标准实验室值和临床检查）。
在 73 例 NSCLC 患者的队列中（平均[SD]年龄，68.1[8.9]岁；44[60%]为男性），25 例（34.2%[95%CI，24.4%-45.7%]）出现了自身免疫性皮肤毒性作用，在完全缓解或部分缓解的患者中更为常见（68.2%[95%CI，47.3%-83.6%]），而在疾病进展或稳定的患者中则不太常见（19.6%[95%CI，11.0%-32.5%]）（χ2=14.02，P<0.001）。在肿瘤组织和皮肤之间鉴定出 9 个共享的 T 细胞抗原。这些抗原能够在体外刺激 CD8+和 CD4+T 细胞。在对抗 PD-1 治疗有反应的患者的血液样本中发现的一些抗原特异性 T 细胞也存在于自身免疫性皮肤病变和肺肿瘤中。
这些发现强调了检查点抑制剂介导的自身免疫毒性作用的潜在机制，并描述了毒性作用与治疗反应之间的关联；这种理解将有助于控制不良反应、破译新的癌症抗原，并进一步改善免疫治疗。
