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

Dung T. Le, Dirk G. Brockstedt, Ran Nir-Paz, Johannes Hampl, Shruti Mathur, John Nemunaitis, Daniel H. Sterman, Raffit Hassan, Eric Lutz, Bentley Moyer, Martin Giedlin, Jana Lynn Louis, Elizabeth A. Sugar, Alice Pons, Andrea L. Cox, Jordana Levine, Aimee Luck Murphy, Peter Illei, Thomas W. Dubensky, Joseph E. EidenElizabeth M. Jaffee, Daniel A. Laheru

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)858-868
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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