title: Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen.
abstract: CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This in vivo functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rafiq
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Purdon
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Daniyan
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Koneru
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute; Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Dao
authors.affiliation: Eureka Therapeutics, Emeryville, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Molecular Pharmacology Program, Sloan Kettering Institute; Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Weill Cornell Medicine, New York, NY, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Weill Cornell Medicine, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Brentjens
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D015234:HLA-A Antigens / Q000032:analysis; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000096:biosynthesis; D007938:Leukemia / Q000628:therapy*; D051379:Mice; D010051:Ovarian Neoplasms / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D059467:Transcriptome; D025721:WT1 Proteins / Q000032:analysis / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D025721:WT1 Proteins; D018664:Interleukin-12