title: Phase I clinical trial of mixed bacterial vaccine (Coley's toxins) in patients with NY-ESO-1 expressing cancers: immunological effects and clinical activity.
abstract: OBJECTIVE
  Mixed bacterial vaccine (MBV, Coley's toxins) is a historical, vaguely defined preparation of heat-inactivated Streptococcus pyogenes and Serratia marcescens used as nonspecific immunotherapy in the treatment of cancer. The mechanism of action is suspected to have an immunologic basis, yet it is poorly defined up to now. We developed a new, biochemically well defined and current good manufacturing practice-compliant MBV preparation, which has been investigated in patients with NY-ESO-1 expressing cancers.
  
  
  METHODS
  Patients received MBV subcutaneously at a starting dose of 250 EU (endotoxin units) twice a week. The MBV dose was escalated in each patient until a body temperature of 38°C to 39.5°C was induced or up to the maximum dose of 547.000 EU. Changes in serum cytokine levels were determined and immune responses to NY-ESO-1 were evaluated. Tumor response was assessed according to RECIST.
  
  
  RESULTS
  Twelve patients were enrolled and 11 of them developed fever after the administration of MBV. Ten of 12 patients showed a consistent increase in serum IL-6 levels with the highest levels coinciding with the highest body temperature. A subgroup of patients showed increasing levels of TNF-α, IFN-γ, and IL1-β. A patient with metastatic bladder cancer showed a partial tumor response strongly correlated with MBV-induced fever and highly elevated levels of several cytokines.
  
  
  CONCLUSIONS
  MBV at fever-inducing dose levels can lead to a massive induction of immunoregulatory cytokines that may be involved in inducing tumor regressions. We propose to further explore the role of MBV as a potent immune modulator at higher dose levels and in conjunction with antigen-specific cancer vaccines.
authors: Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, Frankfurt, Germany.
authors: Julia
authors: J
authors: Karbach
authors: Antje
authors: A
authors: Neumann
authors: Kathrin
authors: K
authors: Brand
authors: Claudia
authors: C
authors: Wahle
authors: Ekkehard
authors: E
authors: Siegel
authors: Markus
authors: M
authors: Maeurer
authors: Erika
authors: E
authors: Ritter
authors: Takamasa
authors: T
authors: Tsuji
authors: Sacha
authors: S
authors: Gnjatic
authors: Lloyd J
authors: LJ
authors: Old
authors: Gerd
authors: G
authors: Ritter
authors: Elke
authors: E
authors: Jäger
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000276:immunology; D001831:Body Temperature; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012706:Serratia marcescens / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000951:Antigens, Neoplasm; D001428:Bacterial Vaccines; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D053583:Interleukin-1beta; D015850:Interleukin-6; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma