title: Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
abstract: OBJECTIVE
  The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.
  
  
  METHODS
  We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.
  
  
  RESULTS
  Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.
  
  
  CONCLUSIONS
  Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892-1201, USA. Mark_Dudley@nih.gov
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Richard
authors.initials: R
authors.lastname: Sherry
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.forename: Richard
authors.initials: R
authors.lastname: Royal
authors.forename: Udai
authors.initials: U
authors.lastname: Kammula
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.forename: JianPing
authors.initials: J
authors.lastname: Huang
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Citrin
authors.forename: Susan F
authors.initials: SF
authors.lastname: Leitman
authors.forename: John
authors.initials: J
authors.lastname: Wunderlich
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Armen
authors.initials: A
authors.lastname: Thomasian
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Downey
authors.forename: Franz O
authors.initials: FO
authors.lastname: Smith
authors.forename: Jacob
authors.initials: J
authors.lastname: Klapper
authors.forename: Kathleen
authors.initials: K
authors.lastname: Morton
authors.forename: Carolyn
authors.initials: C
authors.lastname: Laurencot
authors.forename: Donald E
authors.initials: DE
authors.lastname: White
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000097:blood; D007376:Interleukin-2 / Q000627:therapeutic use*; D015851:Interleukin-7 / Q000097:blood; D053208:Kaplan-Meier Estimate; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D013997:Time Factors; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; C508605:IL7 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine