title: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.
abstract: OBJECTIVE
  We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma.
  
  
  METHODS
  Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL) -2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m(2)). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy.
  
  
  RESULTS
  Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 +/- 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation.
  
  
  CONCLUSIONS
  Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, CRC 3-3940, 10 Center Dr MSC 1201, Bethesda MD 20892-1202, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Udai
authors.initials: U
authors.lastname: Kammula
authors.forename: Don E
authors.initials: DE
authors.lastname: White
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Mavroukakis
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Rogers
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Gracia
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Jones
authors.forename: David P
authors.initials: DP
authors.lastname: Mangiameli
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Pelletier
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.forename: Michael R
authors.initials: MR
authors.lastname: Robinson
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
authors.forename: Armando C
authors.initials: AC
authors.lastname: Filie
authors.forename: Andrea
authors.initials: A
authors.lastname: Abati
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000276:immunology* / Q000628:therapy*; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D007376:Interleukin-2; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine