Listeria monocytogenes (Lm) vectors are being developed for application to cancer and chronic infections due to several attractive features including potent induction of innate and adaptive cellular immunity, activity upon repeat administration, and ease of manufacturing. We have developed an Lm platform strain known as CRS-100, which has 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, 2004. PNAS 101:13832). Treatment of Balb/c mice bearing intraheptic tumor metastases with CRS-100 induced the peripheral recruitment together with the amplification and activation of the hepatic NK cell pool leading to cross-presentation of relevant tumor rejection antigens, priming of a systemic tumor-specific adaptive T cell response, and long-term survival (Bahjat, 2007. J. Immunol. 179:7376). CRS-100 is currently undergoing clinical evaluation in a Phase 1 dose-escalation study. IV infusion of CRS-100 in adults with liver metastases was well tolerated over the doses tested, ranging from 10^6 to 3 x 10^8 CFU. No investigational agent related DLTs or liver toxicities were observed, consistent with toxicology studies conducted in over 60 cynomolgus monkeys. Consistent with a mechanism of leukocyte recruitment following administration of CRS-100, two subjects with evidence of T cell and NK cell count reduction in blood also exhibited upregulation of the cell surface activation marker CD38 on NK cells and CD8+ T cells. Multiple proinflammatory cytokines/chemokines were also elevated in patients following treatment compared to baseline, indicating that CRS-100 was bioactive. CRS-207 is a second Lm strain, comprised of recombinant CRS-100 encoding the tumor-associated antigen Mesothelin. Treatment with CRS-207 conferred therapeutic anti-tumor efficacy in mice and broke T cell tolerance against endogenous Mesothelin in cynomolgus monkeys. The safety and tolerability of CRS-207 is currently being evaluated in an escalating repeat-dose Phase I clinical trial among subjects with cancers expressing Mesothelin, including pancreatic, ovarian, mesothelioma and non-small cell lung cancers. Collectively, CRS-100 and CRS-207 represent unique approaches to invoke potent stimulation of innate and tumor-specific cellular immunity to treat diverse cancers representing significant unmet medical needs.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA