title: Listeria-based cancer vaccines that segregate immunogenicity from toxicity.
abstract: The facultative intracellular bacterium Listeria monocytogenes is being developed as a cancer vaccine platform because of its ability to induce potent innate and adaptive immunity. For successful clinical application, it is essential to develop a Listeria platform strain that is safe yet retains the potency of vaccines based on wild-type bacteria. Here, we report the development of a recombinant live-attenuated vaccine platform strain that retains the potency of the fully virulent pathogen, combined with a >1,000-fold reduction in toxicity, as compared with wild-type Listeria. By selectively deleting two virulence factors, ActA (DeltaactA) and Internalin B (DeltainlB), the immunopotency of Listeria was maintained and its toxicity was diminished in vivo, largely by blocking the direct internalin B-mediated infection of nonphagocytic cells, such as hepatocytes, and the indirect ActA-mediated infection by cell-to-cell spread from adjacent phagocytic cells. In contrast, infection of phagocytic cells was not affected, leaving intact the ability of Listeria to stimulate innate immunity and to induce antigenspecific cellular responses. Listeria DeltaactA/DeltainlB-based vaccines were rapidly cleared from mice after immunization and induced potent and durable effector and memory T-cell responses with no measurable liver toxicity. Therapeutic vaccination of BALB/c mice bearing murine CT26 colon tumor lung metastases or palpable s.c. tumors (>100 mm(3)) with recombinant Listeria DeltaactA/DeltainlB expressing an endogenous tumor antigen resulted in breaking of self-tolerance and long-term survival. We propose that recombinant Listeria DeltaactA/DeltainlB expressing human tumor-associated antigens represents an attractive therapeutic strategy for further development and testing in human clinical trials.
authors.affiliation: Cerus, Concord, CA 94520, USA. dirk_brockstedt@cerus.com
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: Martin A
authors.initials: MA
authors.lastname: Giedlin
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Leong
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: William
authors.initials: W
authors.lastname: Luckett
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: David N
authors.initials: DN
authors.lastname: Cook
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Portnoy
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D012329:RNA, Bacterial / Q000235:genetics; D012347:RNA, Transfer, Arg / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D019496:Cancer Vaccines; D008565:Membrane Proteins; D012329:RNA, Bacterial; D012347:RNA, Transfer, Arg; C095768:inlB protein, Listeria monocytogenes; C072980:actA protein, Listeria monocytogenes