title: Establishment and large-scale expansion of minimally cultured "young" tumor infiltrating lymphocytes for adoptive transfer therapy.
abstract: Treatment of metastatic melanoma patients with adoptively transferred tumor infiltrating lymphocytes (TIL) has developed into an effective therapy. Various studies reported objective responses of 50% and more. The use of unselected, minimally cultured, bulk TIL (Young-TIL) has simplified the TIL production process and may therefore, allow the accessibility of this approach to cancer centers worldwide. This article describes the precise process leading to the large-scale production of Young-TIL for therapy. We have enrolled 55 melanoma patients and optimized their Young-TIL generation process. Young-TIL cultures were successfully established for 51 of 55 (93%) patients in 16.7 ± 5.5 days. In a large-scale expansion procedure Young-TIL of 32 patients were further expanded to treatment levels, resulting in a final number of 4.5 x 10¹⁰ ± 2.0 x 10¹⁰ TIL. Fifteen of 31 (48%) patients, who were evaluated, achieved a clinical response, including 4 complete and 11 partial responses. We confirmed the significant correlation between short culture duration, high number of infused cells, and tumor regression. A high percentage of CD8 T cells in the infusion product was beneficial to achieve an objective response. All responding patients were treated with Young-TIL cultures established in < 20 days. In summary, we describe here an efficient and reliable method to generate Young-TIL for adoptive transfer therapy, which may easily be adopted by other cancer centers and can lead to objective responses in 50% of refractory melanoma patients. In the future this approach may be used also in other types of malignancies.
authors.affiliation: Ella Institute for Treatment and Research of Melanoma, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Itzhaki
authors.forename: Einat
authors.initials: E
authors.lastname: Hovav
authors.forename: Yaara
authors.initials: Y
authors.lastname: Ziporen
authors.forename: Daphna
authors.initials: D
authors.lastname: Levy
authors.forename: Adva
authors.initials: A
authors.lastname: Kubi
authors.forename: Dragoslav
authors.initials: D
authors.lastname: Zikich
authors.forename: Liat
authors.initials: L
authors.lastname: Hershkovitz
authors.forename: Avraham J
authors.initials: AJ
authors.lastname: Treves
authors.forename: Bruria
authors.initials: B
authors.lastname: Shalmon
authors.forename: Douglas
authors.initials: D
authors.lastname: Zippel
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
authors.forename: Ronnie
authors.initials: R
authors.lastname: Shapira-Frommer
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D009367:Neoplasm Staging; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D007371:Interferon-gamma