title: Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma.
abstract: OBJECTIVE
  Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown.
  
  
  METHODS
  Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points.
  
  
  RESULTS
  Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded.
  
  
  CONCLUSIONS
  A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.
authors: Surgery Branch, National Cancer Institute, National Institutes of Health, CRC 3W-5752, 10 Center Dr, Bethesda, MD 20892, USA. mark_dudley@nih.gov
authors: Mark E
authors: ME
authors: Dudley
authors: Colin A
authors: CA
authors: Gross
authors: Robert P T
authors: RP
authors: Somerville
authors: Young
authors: Y
authors: Hong
authors: Nicholas P
authors: NP
authors: Schaub
authors: Shannon F
authors: SF
authors: Rosati
authors: Donald E
authors: DE
authors: White
authors: Debbie
authors: D
authors: Nathan
authors: Nicholas P
authors: NP
authors: Restifo
authors: Seth M
authors: SM
authors: Steinberg
authors: John R
authors: JR
authors: Wunderlich
authors: Udai S
authors: US
authors: Kammula
authors: Richard M
authors: RM
authors: Sherry
authors: James C
authors: JC
authors: Yang
authors: Giao Q
authors: GQ
authors: Phan
authors: Marybeth S
authors: MS
authors: Hughes
authors: Carolyn M
authors: CM
authors: Laurencot
authors: Steven A
authors: SA
authors: Rosenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D002648:Child; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D011446:Prospective Studies; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D007376:Interleukin-2; D007371:Interferon-gamma
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