title: Methods to improve adoptive T-cell therapy for melanoma: IFN-γ enhances anticancer responses of cell products for infusion.
abstract: Further development of adoptive T-cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) has the potential to markedly change the long-term prognosis of patients with metastatic melanoma, and modifications of the original protocol that can improve its clinical efficacy are highly desirable. In this study, we demonstrated that a high in vitro tumor reactivity of infusion products was associated with clinical responses upon adoptive transfer. In addition, we systematically characterized the responses of a series of TIL products to relevant autologous short term-cultured melanoma cell lines from 12 patients. We provide evidence that antitumor reactivity of both CD8(+) and CD4(+) T cells could be enhanced in most TIL products by autologous melanoma sensitization by pretreatment with low-dose IFN-γ. IFN-γ selectively enhanced responses to tumor-associated antigens other than melanoma differentiation antigens. In addition, IFN-γ treatment was invariably associated with restored/increased cancer immunogenicity as demonstrated by upregulation of major histocompatibility complex molecules. These findings suggest a potential synergism between IFN-γ and ACT, and have important implications for clinical development of combination strategies for the treatment of metastatic melanoma.
authors.affiliation: Department of Haematology, Center for Cancer Immune Therapy, Copenhagen University Hospital at Herlev, Herlev, Denmark.
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Morten
authors.initials: M
authors.lastname: Hansen
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Sendrup
authors.forename: Trine Zeeberg
authors.initials: TZ
authors.lastname: Iversen
authors.forename: Eva
authors.initials: E
authors.lastname: Ellebæk
authors.forename: Mads H
authors.initials: MH
authors.lastname: Andersen
authors.forename: Per thor
authors.initials: Pt
authors.lastname: Straten
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008207:Lymphatic Metastasis / Q000473:pathology; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D010865:Pilot Projects; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D007371:Interferon-gamma