title: A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction.
abstract: OBJECTIVE
  Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T-cell responses against mesothelin-expressing murine tumors. These two phase I studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively.
  
  
  METHODS
  A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 × 10(6), 3 × 10(7), or 3 × 10(8) colony-forming units (cfu). CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic, or ovarian cancers. Seventeen subjects received up to 4 doses of 1 × 10(8), 3 × 10(8), 1 × 10(9), or 1 × 10(10) cfu.
  
  
  RESULTS
  A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1 × 10(9) cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, listeriolysin O and mesothelin-specific T-cell responses were detected and 37% of subjects lived ≥15 months.
  
  
  CONCLUSIONS
  ANZ-100 and CRS-207 administration was safe and resulted in immune activation.
authors.affiliation: The Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, Maryland 21231, USA. dle2@jhmi.edu
authors.forename: Dung T
authors.initials: DT
authors.lastname: Le
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: Ran
authors.initials: R
authors.lastname: Nir-Paz
authors.forename: Johannes
authors.initials: J
authors.lastname: Hampl
authors.forename: Shruti
authors.initials: S
authors.lastname: Mathur
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Sterman
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.forename: Eric
authors.initials: E
authors.lastname: Lutz
authors.forename: Bentley
authors.initials: B
authors.lastname: Moyer
authors.forename: Martin
authors.initials: M
authors.lastname: Giedlin
authors.forename: Jana-Lynn
authors.initials: JL
authors.lastname: Louis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sugar
authors.forename: Alice
authors.initials: A
authors.lastname: Pons
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
authors.forename: Jordana
authors.initials: J
authors.lastname: Levine
authors.forename: Aimee Luck
authors.initials: AL
authors.lastname: Murphy
authors.forename: Peter
authors.initials: P
authors.lastname: Illei
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Eiden
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Laheru
mesh_terms: D000328:Adult; D000368:Aged; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D002277:Carcinoma / Q000556:secondary / Q000628:therapy; D016207:Cytokines / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008089:Listeria monocytogenes / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D020714:Maximum Tolerated Dose; D000090204:Mesothelin; D008654:Mesothelioma / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
chemical_list: D001428:Bacterial Vaccines; D019496:Cancer Vaccines; D016207:Cytokines; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D014613:Vaccines, Attenuated; D000090204:Mesothelin