Live-attenuated L. monocytogenes encoding mesothelin for immunotherapy of patients with pancreas and ovarian cancers

1874 Listeria monocytogenes (Lm) is an attractive vector platform due to potent vaccine-induced innate immunity and acquired CD4+/CD8+ T-cell immunity specific for encoded heterologous antigens. We have developed an Lm platform strain known as CRS-100, which has engineered deletions of two genes encoding the virulence determinants actA and internalin B (inlB; Lm ΔactA/ΔinlB), resulting in 1,000-fold attenuation compared to wild-type Lm (Brockstedt et. al. 2004. PNAS 101:13832). CRS-100 is an investigational agent currently undergoing clinical evaluation in a Phase 1 dose-escalation study of safety and tolerability following intravenous administration in adults with carcinoma and liver metastases (VAC05001; clinicaltrials.gov identifier NCT00327652). CRS-207 is a live-attenuated Lm vaccine strain based on CRS-100 that encodes human Mesothelin. Mesothelin is a tumor-associated antigen that is broadly expressed across pancreas and ovarian cancers, but not in normal cells from these organs. Mesothelin-specific cellular immunity correlated with positive clinical outcomes that have been observed in patients with pancreatic carcinoma after vaccination with an allogeneic whole cell vaccine encoding GM-CSF (Jaffee et. al. 2001. JCO, 19:145, and Thomas et. al. 2004. J. Exp. Med. 200:297). In preclinical pharmacology and toxicology studies we show that CRS-207 elicits human Mesothelin-specific CD4+/CD8+ immunity in mice and in Cynomolgus monkeys, and therapeutic efficacy in tumor-bearing mice. Furthermore, immunization strategies utilizing Lm-based vaccine platforms encoding mouse Mesothelin breaks tolerance against the endogenous antigen resulting in significant anti-tumor growth. Repeated intravenous dose safety studies (q3 weeks x 5) in cynomolgus monkeys are in progress. These data to date support the clinical evaluation of CRS-207 for patients with pancreas or ovarian cancer.