title: T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma.
abstract: Pancreatic ductal adenocarcinomas (PDAs) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA.
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.|Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98195.
authors.forename: Ingunn M
authors.initials: IM
authors.lastname: Stromnes
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Schmitt
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Hulbert
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Brockenbrough
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.
authors.forename: Hieu
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Department of Radiology, University of Washington School of Medicine, Seattle, WA, 98195.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cuevas
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Dotson
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98195.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Tan
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hotes
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.|Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98195.|Division of Medical Oncology, University of Washington School of Medicine, Seattle, WA, 98195.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.affiliation: Clinical Research Division, Seattle, WA, 98109.|Public Health Sciences Division of the Fred Hutchinson Cancer Research Center, Seattle, WA, 98109.|Division of Medical Oncology, University of Washington School of Medicine, Seattle, WA, 98195.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D016219:Immunotherapy, Adoptive / Q000379:methods; D019169:Jurkat Cells; D053208:Kaplan-Meier Estimate; D000090204:Mesothelin; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015202:Protein Engineering / Q000379:methods; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000941:Antigens; D058851:GPI-Linked Proteins; D011948:Receptors, Antigen, T-Cell; D000090204:Mesothelin