title: Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies.
abstract: OBJECTIVE
  Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies.
  
  
  METHODS
  Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning.
  
  
  RESULTS
  TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment.
  
  
  CONCLUSIONS
  Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed.
authors.affiliation: Ella Institute of Melanoma, Department of Surgical Oncology, Sheba Medical Center, Ramat Gan, Israel. michal.besser@sheba.health.gov.il
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.forename: Ronnie
authors.initials: R
authors.lastname: Shapira-Frommer
authors.forename: Orit
authors.initials: O
authors.lastname: Itzhaki
authors.forename: Avraham J
authors.initials: AJ
authors.lastname: Treves
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Zippel
authors.forename: Daphna
authors.initials: D
authors.lastname: Levy
authors.forename: Adva
authors.initials: A
authors.lastname: Kubi
authors.forename: Noa
authors.initials: N
authors.lastname: Shoshani
authors.forename: Dragoslav
authors.initials: D
authors.lastname: Zikich
authors.forename: Yaara
authors.initials: Y
authors.lastname: Ohayon
authors.forename: Daniel
authors.initials: D
authors.lastname: Ohayon
authors.forename: Bruria
authors.initials: B
authors.lastname: Shalmon
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
authors.forename: Ronit
authors.initials: R
authors.lastname: Yerushalmi
authors.forename: Sara
authors.initials: S
authors.lastname: Apter
authors.forename: Alon
authors.initials: A
authors.lastname: Ben-Nun
authors.forename: Eytan
authors.initials: E
authors.lastname: Ben-Ami
authors.forename: Avichai
authors.initials: A
authors.lastname: Shimoni
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D064987:Cell- and Tissue-Based Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab