期刊
CLINICAL CANCER RESEARCH
卷 18, 期 3, 页码 858-868出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-11-2121
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类别
资金
- American Society of Clinical Oncology
- NIH/GI SPORE [2P50 CA062924]
- NIH/NCI [T32 CA009243]
- NCI [K23 CA093566-01A1]
- Viragh Family Foundation
Purpose: Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm Delta actA/Delta inlB). 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 Delta actA/Delta inlB 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 1 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 x 10(6), 3 x 10(7), or 3 x 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 x 10(8), 3 x 10(8), 1 x 10(9), or 1 x 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 x 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 0 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. Gin Cancer Res; 18(3); 858-68. (C) 2011 AACR.
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