Li Hong, Ma Weijie, Yoneda Ken Y, Moore Elizabeth H, Zhang Yanhong, Pu Lee L Q, Frampton Garrett M, Molmen Michael, Stephens Philip J, Li Tianhong
Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA.
Department of Geriatrics, Peking University First Hospital, Beijing, China.
J Hematol Oncol. 2017 Feb 28;10(1):64. doi: 10.1186/s13045-017-0433-z.
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.
程序性细胞死亡蛋白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及越来越多其他癌症类型患者的标准治疗方案。在本报告中，我们讨论了一名转移性肺鳞状细胞癌（SCC）患者的临床病史、病理评估和基因组学发现，该患者在接受三剂纳武利尤单抗治疗后出现严重的纳武利尤单抗诱导的肺炎，随后实现了持久的临床缓解。
一名化疗难治性转移性肺SCC患者在接受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。尽管在三剂后停用了纳武利尤单抗，并使用高剂量口服糖皮质激素治疗3级肺炎，但影像学评估显示肿瘤持续反应，3个月时达到完全缓解。在提交本报告时，该患者已保持临床缓解14个月。免疫组织化学染色显示，在肺炎和复发性肿瘤标本中，肺泡内巨噬细胞和存活肿瘤细胞分别高表达PD-L1。通过FoundationOne靶向外显子组测序进行的肿瘤基因组分析显示，肿瘤突变负荷（TMB）非常高，在肺SCC中处于第95-96百分位，即在纳武利尤单抗治疗前和治疗后的肿瘤标本中分别为87.4-91.0和82.9个突变/Mb。除了一个之外，在诊断、复发和治疗后复发的肿瘤标本中，13个功能性基因组改变保持不变，这表明纳武利尤单抗重新设定了患者针对一种或多种预先存在的肿瘤相关抗原（TAA）的免疫系统。一个潜在的TAA候选者是端粒酶逆转录酶（TERT），其中检测到一个致癌启动子-146C>T突变。人类白细胞抗原（HLA）分型显示为HLA-A*0201纯合子，这是一种常见的HLA I类等位基因，已被用于开发针对TERT衍生肽的通用癌症疫苗。
在这名化疗难治性肺SCC患者中，纳武利尤单抗可以迅速重新设定并维持宿主针对预先存在的TAA的免疫力。需要进一步开展机制研究，以确定有效的免疫细胞，明确HLA限制的TAA以及负责强效抗肿瘤作用的特定T细胞受体克隆，目的是开发有效性和安全性更高的精准免疫疗法。
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