title: Persistence of CTL clones targeting melanocyte differentiation antigens was insufficient to mediate significant melanoma regression in humans.
abstract: OBJECTIVE
  Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable cancer regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8(+) T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively.
  
  
  METHODS
  We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8(+) T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2(+) treatment-refractory metastatic melanoma received highly avid MDA-specific CD8(+) T-cell clones specific for either gp100 (n = 10) or MART-1 (n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen.
  
  
  RESULTS
  Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria.
  
  
  CONCLUSIONS
  Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Smita S
authors.initials: SS
authors.lastname: Chandran
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Biman C
authors.initials: BC
authors.lastname: Paria
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Luke D
authors.initials: LD
authors.lastname: Rothermel
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stephens
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Somerville
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. udai_kammula@nih.gov.
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003872:Dermatitis / Q000209:etiology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D058965:MART-1 Antigen / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D058950:Melanoma-Specific Antigens / Q000276:immunology*; D008875:Middle Aged; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden; D058951:gp100 Melanoma Antigen / Q000276:immunology
chemical_list: D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; D058950:Melanoma-Specific Antigens; D058951:gp100 Melanoma Antigen