title: Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo.
abstract: Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of CD4(+) and CD8(+) naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets (CD4(+)/CD8(+) naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent CD4(+) and CD8(+) CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies.
authors.affiliation: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sommermeyer
authors.affiliation: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Medicine II - Hematology and Medical Oncology, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hudecek
authors.affiliation: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Kosasih
authors.affiliation: Department of Medicine II - Hematology and Medical Oncology, University of Würzburg, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gogishvili
authors.affiliation: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Maloney
authors.affiliation: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Turtle
authors.affiliation: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Medicine, University of Washington, Seattle, WA, USA.|Institute for Advanced Study, Technical University of Munich, Munich, Germany.
authors.forename: S R
authors.initials: SR
authors.lastname: Riddell
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins