title: IDO and galectin-3 hamper the ex vivo generation of clinical grade tumor-specific T cells for adoptive cell therapy in metastatic melanoma.
abstract: Adoptive T cell transfer (ACT) with ex vivo-expanded tumor-reactive T cells proved to be successful for the treatment of metastatic melanoma patients. Mixed lymphocyte tumor cell cultures (MLTC) can be used to generate tumor-specific T cells for ACT; however, in a number of cases tumor-reactive T cell, expansion is far from optimal. We hypothesized that this is due to tumor intrinsic and extrinsic factors and aimed to identify and manipulate these factors so to optimize our clinical, GMP-compliant MLTC protocol. We found that the tumor cell produced IDO and/or galectin-3, and the accumulation of CD4+CD25hiFoxP3+T cells suppressed the expansion of tumor-specific T cells in the MLTC. Strategies to eliminate CD4+CD25hiFoxP3+T cells during culture required the depletion of the whole CD4+T cell population and were found to be undesirable. Blocking of IDO and galectin-3 was feasible and resulted in improved efficiency of the MLTC. Implementation of these findings in clinical protocols for ex vivo expansion of tumor-reactive T cells holds promise for an increased therapeutic potential of adoptive cell transfer treatments with tumor-specific T cells.
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Melief
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: Visser
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. e.verdegaal@lumc.nl.|Department of Clinical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. e.verdegaal@lumc.nl.
authors.forename: Els M E
authors.initials: EME
authors.lastname: Verdegaal
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D005434:Flow Cytometry; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology* / Q000637:transplantation; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D037502:Galectin 3; C508017:IL2RA protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma
keywords: Adoptive cell transfer; GMP; Galectin-3; IDO; Immunotherapy; Metastatic melanoma