title: Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma.
abstract: OBJECTIVE
  Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site.
  
  
  METHODS
  Thirty-three patients with metastatic melanoma were treated in a cell dose-escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered.
  
  
  RESULTS
  The administration of 0.001 to 0.1 × 10(9) NFAT.IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10(9) cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability.
  
  
  CONCLUSIONS
  In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Joal D
authors.initials: JD
authors.lastname: Beane
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sadik H
authors.initials: SH
authors.lastname: Kassim
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Azam V
authors.initials: AV
authors.lastname: Nahvi
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Lien T
authors.initials: LT
authors.lastname: Ngo
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Giao Q
authors.initials: GQ
authors.lastname: Phan
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Toomey
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sid P
authors.initials: SP
authors.lastname: Kerkar
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. sar@mail.nih.gov.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology* / Q000637:transplantation; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015533:Transcriptional Activation; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018664:Interleukin-12