title: Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients.
abstract: OBJECTIVE
  Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability. Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients. The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.
  
  
  METHODS
  Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.
  
  
  RESULTS
  Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.
  
  
  CONCLUSIONS
  We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer.
authors.affiliation: Ella Institute of Melanoma, Sheba Medical Center, Tel-Hashomer, 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: Avraham J
authors.initials: AJ
authors.lastname: Treves
authors.forename: Dov
authors.initials: D
authors.lastname: Zippel
authors.forename: Orit
authors.initials: O
authors.lastname: Itzhaki
authors.forename: Liat
authors.initials: L
authors.lastname: Hershkovitz
authors.forename: Daphna
authors.initials: D
authors.lastname: Levy
authors.forename: Adva
authors.initials: A
authors.lastname: Kubi
authors.forename: Einat
authors.initials: E
authors.lastname: Hovav
authors.forename: Natalia
authors.initials: N
authors.lastname: Chermoshniuk
authors.forename: Bruria
authors.initials: B
authors.lastname: Shalmon
authors.forename: Izhar
authors.initials: I
authors.lastname: Hardan
authors.forename: Raphael
authors.initials: R
authors.lastname: Catane
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
authors.forename: Sara
authors.initials: S
authors.lastname: Apter
authors.forename: Alon
authors.initials: A
authors.lastname: Ben-Nun
authors.forename: Iryna
authors.initials: I
authors.lastname: Kuchuk
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: D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000276:immunology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use; D007902:Length of Stay; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007376:Interleukin-2