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

Clin Cancer Res. 2012 Feb 1;18(3):858-68. doi: 10.1158/1078-0432.CCR-11-2121. Epub 2011 Dec 6.

Abstract

Purpose: 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.

Experimental design: 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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bacterial Vaccines / administration & dosage*
  • Bacterial Vaccines / adverse effects
  • Bacterial Vaccines / immunology*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / immunology*
  • Carcinoma / secondary
  • Carcinoma / therapy
  • Cytokines / blood
  • Female
  • Flow Cytometry
  • GPI-Linked Proteins / immunology*
  • Humans
  • Immunohistochemistry
  • Listeria monocytogenes / immunology*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary
  • Liver Neoplasms / therapy*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Male
  • Maximum Tolerated Dose
  • Mesothelioma / pathology
  • Mesothelioma / therapy
  • Middle Aged
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy
  • Vaccines, Attenuated / administration & dosage
  • Vaccines, Attenuated / adverse effects
  • Vaccines, Attenuated / immunology

Substances

  • Bacterial Vaccines
  • Cancer Vaccines
  • Cytokines
  • GPI-Linked Proteins
  • Vaccines, Attenuated
  • mesothelin