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

• Published in: Clinical cancer research 2012-02, Vol.18 (3), p.858-868
• Main Authors: LE, Dung T, BROCKSTEDT, Dirk G, GIEDLIN, Martin, LOUIS, Jana-Lynn, SUGAR, Elizabeth A, PONS, Alice, COX, Andrea L, LEVINE, Jordana, LUCK MURPHY, Aimee, ILLEI, Peter, DUBENSKY, Thomas W, EIDEN, Joseph E, NIR-PAZ, Ran, JAFFEE, Elizabeth M, LAHERU, Daniel A, HAMPL, Johannes, MATHUR, Shruti, NEMUNAITIS, John, STERMAN, Daniel H, HASSAN, Raffit, LUTZ, Eric, MOYER, Bentley
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Bacterial Vaccines - administration & dosage; Bacterial Vaccines - adverse effects; Bacterial Vaccines - immunology; Biological and medical sciences; 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; 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; Medical sciences; Mesothelin; Mesothelioma - pathology; Mesothelioma - therapy; Middle Aged; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Pharmacology. Drug treatments; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - adverse effects; Vaccines, Attenuated - immunology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-2121

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. 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. 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. ANZ-100 and CRS-207 administration was safe and resulted in immune activation.