title: Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma.
abstract: This report describes a phase I study of the adoptive transfer of cloned melanoma antigen-specific T lymphocytes for therapy of patients with advanced melanoma. Clones were derived from peripheral blood lymphocytes or tumor-infiltrating lymphocytes of patients who had received prior immunization with the melanoma-associated antigen, gpl00. In response to its cognate antigen, each clone used for treatment secreted large amounts of interferon-gamma and granulocyte-macrophage colony-stimulating factor, lesser amounts of interleukin (IL)-2 and tumor necrosis factor-alpha, and little or no IL-4 and IL-10. Clones also demonstrated recognition of human leukocyte antigen-matched melanomas using cytokine secretion and lysis assays. Twelve patients received 2 cycles of cells alone; 11 patients received additional cycles of cells and were randomized between two schedules of IL-2 (125,000 IU/kg subcutaneously daily for 12 days versus 720,000 IU/kg intravenously every 8 h for 4 days). A total of 51 cycles of cells were administered, with an average of 1 x 10(10) cells per cycle. Peripheral blood samples were analyzed for persistence of transferred cells by T-cell receptor-specific polymerase chain reaction. Transferred cells reached a maximum level at 1 h after transfer but rapidly declined to undetectable levels by 2 weeks. One minor response and one mixed response were observed (both in the high-dose IL-2 arm). This report demonstrates the safety and feasibility of cloned T-cell transfer as a therapy for patients with cancer. The lack of clinical effectiveness of this protocol suggests that transfer of different or additional cell types or that modulation of the recipient host environment is required for successful therapy.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1502, USA. mark_dudley@nih.gov
authors.forename: M E
authors.initials: ME
authors.lastname: Dudley
authors.forename: J
authors.initials: J
authors.lastname: Wunderlich
authors.forename: M I
authors.initials: MI
authors.lastname: Nishimura
authors.forename: D
authors.initials: D
authors.lastname: Yu
authors.forename: J C
authors.initials: JC
authors.lastname: Yang
authors.forename: S L
authors.initials: SL
authors.lastname: Topalian
authors.forename: D J
authors.initials: DJ
authors.lastname: Schwartzentruber
authors.forename: P
authors.initials: P
authors.lastname: Hwu
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola
authors.forename: R
authors.initials: R
authors.lastname: Sherry
authors.forename: S F
authors.initials: SF
authors.lastname: Leitman
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D002999:Clone Cells; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology*; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D058951:gp100 Melanoma Antigen
chemical_list: D007376:Interleukin-2; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma