Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report.
Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report.
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DOI：
10.1186/s13045-017-0433-z
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发表时间：
2017-02-28
影响因子：
28.5
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Li H;Ma W;Yoneda KY;Moore EH;Zhang Y;Pu LL;Frampton GM;Molmen M;Stephens PJ;Li T
程序性细胞死亡1（PD-1）及其配体1（PD-L1）抑制剂已迅速成为晚期非小细胞肺癌和越来越多的其他癌症类型患者的标准治疗。在这份报告中，我们讨论了转移性肺鳞状细胞癌（SCC）患者的临床病史、病理学评价和基因组发现，该患者在三次nivolumab给药后出现严重的nivolumab诱导的肺炎，随后出现持久的临床缓解。1例化疗难治性转移性肺SCC患者在纳武利尤单抗治疗后第4周出现症状性肺炎，同时出现强效抗肿瘤反应。尽管在三次给药后停用纳武利尤单抗，并使用高剂量口服皮质类固醇治疗3级肺炎，但通过放射学评估，3个月时肿瘤对完全缓解的持续反应是明显的。在本次提交时，患者已保持临床缓解14个月。通过免疫组织化学染色，分别在肺炎和复发性肿瘤标本的肺泡内巨噬细胞和活肿瘤细胞中观察到高PD-L1表达。通过FoundationOne靶向外显子组测序进行的肿瘤基因组谱分析显示了非常高的肿瘤突变负荷（TMB），对应于肺SCC中的95-96百分位数，即，在nivolumab治疗前和治疗后的肿瘤标本中，分别为87.4-91.0和82.9 mut/Mb。除了一个，13个功能性基因组改变在诊断、复发和治疗后复发肿瘤标本中保持不变，表明纳武单抗重置了患者的免疫系统对抗一种或多种预先存在的肿瘤相关抗原（TAA）。一种潜在的TAA候选物是端粒酶逆转录酶（TERT），其中检测到致癌启动子-146C>T突变。人类白细胞抗原（HLA）分型显示HLA-A*0201纯合性，这是普遍存在的HLA I类等位基因，已用于开发针对TLR衍生肽的通用癌症疫苗。纳武利尤单抗可以快速重置并维持该化疗难治性肺SCC患者中针对预先存在的TAA的宿主免疫力。需要进一步的机制研究来表征有效的免疫细胞，并确定负责有效抗肿瘤作用的HLA限制性TAA和特异性T细胞受体克隆，目的是开发具有更高有效性和安全性的精确免疫治疗。
Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) inhibitors have quickly become standard of care for patients with advanced non-small cell lung cancer and increasing numbers of other cancer types. In this report, we discuss the clinical history, pathological evaluation, and genomic findings in a patient with metastatic lung squamous cell cancer (SCC) who developed severe nivolumab-induced pneumonitis preceding durable clinical remission after three doses of nivolumab. A patient with chemotherapy-refractory, metastatic lung SCC developed symptomatic pneumonitis by week 4 after nivolumab treatment, concurrently with onset of a potent antitumor response. Despite discontinuation of nivolumab after three doses and the use of high dose oral corticosteroids for grade 3 pneumonitis, continued tumor response to a complete remission by 3 months was evident by radiographic assessment. At the time of this submission, the patient has remained in clinical remission for 14 months. High PD-L1 expression by immunohistochemistry staining was seen in intra-alveolar macrophages and viable tumor cells in the pneumonitis and recurrent tumor specimens, respectively. Tumor genomic profiling by FoundationOne targeted exome sequencing revealed a very high tumor mutation burden (TMB) corresponding to 95–96 percentile in lung SCC, i.e., 87.4–91.0 and 82.9 mut/Mb, respectively, in pre- and post-nivolumab tumor specimens. Except for one, the 13 functional genomic alterations remained the same in the diagnostic, recurrent, and post-treatment, relapsed tumor specimens, suggesting that nivolumab reset the patient’s immune system against one or more preexisting tumor-associated antigens (TAAs). One potential TAA candidate is telomerase reverse transcriptase (TERT) in which an oncogenic promoter -146C>T mutation was detected. Human leukocyte antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA class I allele that has been used to develop universal cancer vaccine targeting TERT-derived peptides. Nivolumab could quickly reset and sustain host immunity against preexisting TAA(s) in this chemotherapy-refractory lung SCC patient. Further mechanistic studies are needed to characterize the effective immune cells and define the HLA-restricted TAA(s) and the specific T cell receptor clones responsible for the potent antitumor effect, with the aim of developing precision immunotherapy with improved effectiveness and safety.