title: Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6.
abstract: OBJECTIVE
  The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV(+) tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV(+) tumor cells.
  
  
  METHODS
  T-cell responses against the HPV-16 oncoproteins were investigated in a patient with an ongoing 22-month disease-free interval after her second resection of distant metastatic anal cancer. T cells genetically engineered to express an oncoprotein-specific TCR from this patient's tumor-infiltrating T cells were tested for specific reactivity against HPV(+) epithelial tumor cells.
  
  
  RESULTS
  We identified, from an excised metastatic anal cancer tumor, T cells that recognized an HLA-A*02:01-restricted epitope of HPV-16 E6. The frequency of the dominant T-cell clonotype from these cells was approximately 400-fold greater in the patient's tumor than in her peripheral blood. T cells genetically engineered to express the TCR from this clonotype displayed high avidity for an HLA-A*02:01-restricted epitope of HPV-16, and they showed specific recognition and killing of HPV-16(+) cervical, and head and neck cancer cell lines.
  
  
  CONCLUSIONS
  These findings demonstrate that HPV-16(+) tumors can be targeted by E6-specific TCR gene engineered T cells, and they provide the foundation for a novel cellular therapy directed against HPV-16(+) malignancies, including cervical, oropharyngeal, anal, vulvar, vaginal, and penile cancers.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Draper
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mei Li M
authors.initials: ML
authors.lastname: Kwong
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sanja
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Tran
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sid
authors.initials: S
authors.lastname: Kerkar
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Hinrichs@nih.gov.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hinrichs
mesh_terms: D001005:Anus Neoplasms / Q000209:etiology / Q000473:pathology; D002277:Carcinoma / Q000209:etiology* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D019672:Genes, T-Cell Receptor; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic; D002583:Uterine Cervical Neoplasms / Q000209:etiology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins