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Selective Targeting of Antitumor Immune Responses with Engineered Live-Attenuated Listeria monocytogenes

¹ Immunology and Hematopoiesis Division, Department of Medical Oncology, Sidney Kimmel Cancer Center; ² Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland; ³ Department of Surgery II, Yamaguchi University School of Medicine, Yamaguchi, Japan; ⁴ Cerus Corp., Concord, California; and ⁵ Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Richard D. Schulick, Department of Surgery and Oncology, Johns Hopkins Medical Institutions, The Bunting-Blaustein Cancer Research Building, Suite 442, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-614-9879; Fax: 410-614-9882; E-mail: rschulick{at}jhmi.edu.

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. (Cancer Res 2006; 66(2): 1096-104)

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