PMID- 28245875 OWN - NLM STAT- MEDLINE DCOM- 20171205 LR - 20181202 IS - 1756-8722 (Electronic) IS - 1756-8722 (Linking) VI - 10 IP - 1 DP - 2017 Feb 28 TI - Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report. PG - 64 LID - 10.1186/s13045-017-0433-z [doi] LID - 64 AB - BACKGROUND: 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. CASE PRESENTATION: 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. CONCLUSIONS: 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. FAU - Li, Hong AU - Li H AD - 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. AD - Department of Geriatrics, Peking University First Hospital, Beijing, China. FAU - Ma, Weijie AU - Ma W AD - 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. FAU - Yoneda, Ken Y AU - Yoneda KY AD - Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA, USA. AD - Department of Internal Medicine, Veterans Affairs Northern California Health Care System, Mather, CA, USA. FAU - Moore, Elizabeth H AU - Moore EH AD - Department of Radiology, University of California Davis School of Medicine, Sacramento, CA, USA. FAU - Zhang, Yanhong AU - Zhang Y AD - Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA. FAU - Pu, Lee L Q AU - Pu LL AD - Division of Plastic Surgery, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA, USA. FAU - Frampton, Garrett M AU - Frampton GM AD - Foundation Medicine, Inc., Cambridge, MA, USA. FAU - Molmen, Michael AU - Molmen M AD - Foundation Medicine, Inc., Cambridge, MA, USA. FAU - Stephens, Philip J AU - Stephens PJ AD - Foundation Medicine, Inc., Cambridge, MA, USA. FAU - Li, Tianhong AU - Li T AD - 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. thli@ucdavis.edu. AD - Department of Internal Medicine, Veterans Affairs Northern California Health Care System, Mather, CA, USA. thli@ucdavis.edu. LA - eng PT - Case Reports PT - Journal Article DEP - 20170228 PL - England TA - J Hematol Oncol JT - Journal of hematology & oncology JID - 101468937 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) RN - 31YO63LBSN (Nivolumab) SB - IM MH - Aged MH - Antibodies, Monoclonal/*adverse effects/therapeutic use MH - Antigens, Neoplasm/analysis MH - Antineoplastic Agents/*adverse effects/therapeutic use MH - B7-H1 Antigen/analysis MH - Carcinoma, Non-Small-Cell Lung/complications/*drug therapy/immunology/pathology MH - Carcinoma, Squamous Cell/complications/*drug therapy/immunology/pathology MH - Humans MH - Immunity/drug effects MH - Lung Neoplasms/complications/*drug therapy/immunology/pathology MH - Male MH - Neoplasm Metastasis MH - Nivolumab MH - Pneumonia/*chemically induced MH - Remission Induction/methods PMC - PMC5331657 OTO - NOTNLM OT - Cancer immunotherapy OT - Complete remission OT - HLA OT - Immune-related adverse event OT - Nivolumab OT - PD-1 inhibitor OT - Pneumonitis OT - Targeted exome sequencing OT - Tumor genomic profiling OT - Tumor mutation burden EDAT- 2017/03/02 06:00 MHDA- 2017/12/06 06:00 PMCR- 2017/02/28 CRDT- 2017/03/02 06:00 PHST- 2017/01/16 00:00 [received] PHST- 2017/02/24 00:00 [accepted] PHST- 2017/03/02 06:00 [entrez] PHST- 2017/03/02 06:00 [pubmed] PHST- 2017/12/06 06:00 [medline] PHST- 2017/02/28 00:00 [pmc-release] AID - 10.1186/s13045-017-0433-z [pii] AID - 433 [pii] AID - 10.1186/s13045-017-0433-z [doi] PST - epublish SO - J Hematol Oncol. 2017 Feb 28;10(1):64. doi: 10.1186/s13045-017-0433-z.