title: Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.
abstract: OBJECTIVE
  Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
  
  
  METHODS
  Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined.
  
  
  RESULTS
  Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified.
  
  
  CONCLUSIONS
  These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.
authors.affiliation: Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. lradvanyi@mdanderson.org
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Radvanyi
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.forename: Minying
authors.initials: M
authors.lastname: Zhang
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Fox
authors.forename: Priscilla
authors.initials: P
authors.lastname: Miller
authors.forename: Jessica
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authors.lastname: Chacon
authors.forename: Richard
authors.initials: R
authors.lastname: Wu
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizee
authors.forename: Sandy
authors.initials: S
authors.lastname: Mahoney
authors.forename: Gladys
authors.initials: G
authors.lastname: Alvarado
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
authors.forename: Valen E
authors.initials: VE
authors.lastname: Johnson
authors.forename: John D
authors.initials: JD
authors.lastname: McMannis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Shpall
authors.forename: Victor
authors.initials: V
authors.lastname: Prieto
authors.forename: Nicholas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Kevin
authors.initials: K
authors.lastname: Kim
authors.forename: Jade
authors.initials: J
authors.lastname: Homsi
authors.forename: Agop
authors.initials: A
authors.lastname: Bedikian
authors.forename: Wen-Jen
authors.initials: WJ
authors.lastname: Hwu
authors.forename: Sapna
authors.initials: S
authors.lastname: Patel
authors.forename: Merrick I
authors.initials: MI
authors.lastname: Ross
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.forename: Anthony
authors.initials: A
authors.lastname: Lucci
authors.forename: Richard
authors.initials: R
authors.lastname: Royal
authors.forename: Janice N
authors.initials: JN
authors.lastname: Cormier
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Rahmatu
authors.initials: R
authors.lastname: Mansaray
authors.forename: Orenthial J
authors.initials: OJ
authors.lastname: Fulbright
authors.forename: Christopher
authors.initials: C
authors.lastname: Toth
authors.forename: Renjith
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Seth
authors.initials: S
authors.lastname: Wardell
authors.forename: Audrey
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D002478:Cells, Cultured; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000627:therapeutic use*; D016131:Lymphocyte Subsets / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D012074:Remission Induction; D012878:Skin Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000637:transplantation*; D016615:Telomere / Q000378:metabolism; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D047368:Tumor Burden / Q000276:immunology
chemical_list: D007376:Interleukin-2