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

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 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 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. 17 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.

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

“…The vaccine was administered as a poly(I:C) (50 mg/ mouse) and OVA protein (2-11 nmol/mouse) mixture as previously described (27). A Listeria monocytogenes-based vaccine engineered to express human mesothelin (CRS-207) was obtained from Anza Therapeutics (28).…”

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

“…MORAb-009 (amatuximab), a chimeric anti-mesothelin monoclonal antibody, SS1P, a recombinant anti-mesothelin immunotoxin, and CRS-207, a live-attenuated Listeria vaccine expressing mesothelin engineered for targeted elimination of mesothelin-expressing cells, are all in clinical trials (18)(19)(20). The nonhuman origin renders recombinant immunotoxins highly immunogenic inducing the generation of neutralizing antibodies and thereby preventing multiple treatments.…”

Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma

“…Clinical trials with dendritic cells (DC) vaccination and live-attenuated Listeria vaccine have shown encouraging results and are being considered for multicenter phase II trials (19,20). Several trials targeting mesothelin have also been conducted or are ongoing with antibody-based therapeutic agents or T-cell therapies (21).…”