title: Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma.
abstract: BACKGROUND
  Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma.
  
  
  METHODS
  Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 microg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The gamma-interferon (IFNgamma) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8.
  
  
  RESULTS
  Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNgamma-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years.
  
  
  CONCLUSIONS
  Treatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-microg dose level was shown to be practical for further study.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA. omar.eton@bmc.org
authors.forename: Omar
authors.initials: O
authors.lastname: Eton
authors.forename: Merrick I
authors.initials: MI
authors.lastname: Ross
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: East
authors.forename: Paul F
authors.initials: PF
authors.lastname: Mansfield
authors.forename: Nicholas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Julie A
authors.initials: JA
authors.lastname: Ellerhorst
authors.forename: Agop Y
authors.initials: AY
authors.lastname: Bedikian
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D006360:Heat-Shock Proteins / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D053208:Kaplan-Meier Estimate; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008875:Middle Aged; D009362:Neoplasm Metastasis; D055815:Young Adult
chemical_list: D019496:Cancer Vaccines; D006360:Heat-Shock Proteins; C484813:vitespin