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 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 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 1x10(6), 3x10(7), or 3x10(8) colony forming units [cfu]. CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic or ovarian cancers. 17 subjects received up to 4 doses of 1x10(8), 3x10(8), 1x10(9), or 1x10(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 1x10(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.