title: Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes.
abstract: Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.
authors.affiliation: Immunology and Hematopoiesis Division, Department of Medical Oncology, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Ajay
authors.initials: A
authors.lastname: Jain
authors.forename: Heather E
authors.initials: HE
authors.lastname: Allen
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Laird
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Chia
authors.forename: Sowmya
authors.initials: S
authors.lastname: Ravi
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: Martin A
authors.initials: MA
authors.lastname: Giedlin
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Leong
authors.forename: Jill E
authors.initials: JE
authors.lastname: Slansky
authors.forename: David N
authors.initials: DN
authors.lastname: Cook
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D005818:Genetic Engineering; D006505:Hepatitis / Q000821:virology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation; D008089:Listeria monocytogenes / Q000235:genetics* / Q000472:pathogenicity; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes
chemical_list: D019496:Cancer Vaccines