American Association for Cancer Research
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Supplementary Figure 2 from 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

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posted on 2023-03-31, 16:46 authored by 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. Eiden, Elizabeth M. Jaffee, Daniel A. Laheru

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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 × 106, 3 × 107, or 3 × 108 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 × 108, 3 × 108, 1 × 109, or 1 × 1010 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 × 109 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. Clin Cancer Res; 18(3); 858–68. ©2011 AACR.

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