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

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2011 Dec 8

PMID 22147941

Citations 197

Authors

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 Jr

Joseph E Eiden

Elizabeth M Jaffee

Daniel A Laheru

Affiliations

Soon will be listed here.

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.

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