title: TGF-beta1 induces preferential rapid expansion and persistence of tumor antigen-specific CD8+ T cells for adoptive immunotherapy.
abstract: Adoptive cell transfer of expanded, autologous tumor-infiltrating lymphocytes (TIL) into lymphodepleted melanoma patients can induce the regression of bulky, metastatic disease. To generate the large numbers of T cells needed for infusion, TIL undergo a rapid expansion protocol (REP) in vitro using anti-CD3 antibody, interleukin-2, and irradiated peripheral blood feeder cells that typically results in an approximately 1000-fold expansion over 14 days. However, we have found that the conventional REP (C-REP) often favors the expansion of CD4+ T cells at the expense of tumor antigen-specific CD8+ T cells, which are the most potent cytolytic effector cells. In this study, we demonstrate that addition of transforming growth factor (TGF)-beta1 to the TIL culture at the onset of rapid expansion (T-REP ) maintained the percentage of CD8+ T cells while not inhibiting overall T-cell expansion. Of T cells expanded from different melanoma patient tumors, 13 of 15 TIL demonstrated improved yields and percentages of both CD8+ and MART-1 melanoma antigen-specific T cells after 14 days of expansion in TGF-beta1 compared with the C-REP. This was associated with a marked improvement in the antitumor activity of the resulting bulk TIL culture in terms of interferon-gamma production and melanoma tumor-specific cytotoxic T-lymphocyte activity. In addition, T-REP T cells demonstrated a higher potential for continued expansion in vitro for up to 3 weeks after the expansion compared with C-REP T cells, suggesting that they may also be capable of increased persistence after adoptive cell transfer. Our results suggest that TGF-beta1-expanded TIL have attributes that might predict efficacy superior to that of conventional TIL.
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liu
authors.forename: Tamara
authors.initials: T
authors.lastname: Etto
authors.forename: Tania
authors.initials: T
authors.lastname: Rodríguez-Cruz
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.forename: Chenghan
authors.initials: C
authors.lastname: Wu
authors.forename: Orenthial J
authors.initials: OJ
authors.lastname: Fulbright
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Laszlo
authors.initials: L
authors.lastname: Radvanyi
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma