title: Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Weijie
authors.initials: W
authors.lastname: Ma
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA, USA.|Department of Internal Medicine, Veterans Affairs Northern California Health Care System, Mather, CA, USA.
authors.forename: Ken Y
authors.initials: KY
authors.lastname: Yoneda
authors.affiliation: Department of Radiology, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Moore
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Plastic Surgery, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA, USA.
authors.forename: Lee L Q
authors.initials: LL
authors.lastname: Pu
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Molmen
authors.affiliation: Foundation Medicine, Inc., Cambridge, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: 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.|Department of Internal Medicine, Veterans Affairs Northern California Health Care System, Mather, CA, USA. thli@ucdavis.edu.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000032:analysis; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007109:Immunity / Q000187:drug effects; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D009362:Neoplasm Metastasis; D000077594:Nivolumab; D011014:Pneumonia / Q000139:chemically induced*; D012074:Remission Induction / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D000077594:Nivolumab
keywords: Cancer immunotherapy; Complete remission; HLA; Immune-related adverse event; Nivolumab; PD-1 inhibitor; Pneumonitis; Targeted exome sequencing; Tumor genomic profiling; Tumor mutation burden