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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-02-0391.
Submitted February 6, 2002
Accepted August 20, 2002
Immunotherapy with a post-transcriptionally modified DNA vaccine induces complete protection against metastatic neuroblastoma
Ursula Pertl, Harald Wodrich, J Michael Ruehlmann, Stephen D Gillies, Holger N Lode, and Ralph A Reisfeld*
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
EMD-Lexigen Reseach Center, Bedford, MA, USA
Department of Pediatrics, Charite Children's Hospital, Berlin, Germany; Lexigen Pharmaceuticals, Inc., Lexington, MA, USA
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA; Pediatrics, Charite Children's Hospital, Berlin, Germany, Germany
* Corresponding author; email: reisfeld{at}scripps.edu.
The successful induction of a T-cell-mediated tumor protective immunity against poorly immunogenic malignancies remains a major challenge for cancer immunotherapy. We achieved this by immunization with a Tyrosine Hydroxylase (mTH) based-DNA vaccine, enhanced with the post-transcriptional regulatory acting RNA element (WPRE), derived from Woodchuck Hepatitis Virus in combination with an antibody-cytokine fusion protein (ch14.18-IL-2) that targets IL-2 to the tumor microenvironment. This DNA vaccine mTH-WPRE, was carried by attenuated Salmonella typhimurium and applied by oral gavage in a mouse model of neuroblastoma. Mice, immunized with the mTH-WPRE vaccine, that additionally received a boost with suboptimal doses of ch14.18-IL-2 were completely protected against hepatic neuroblastoma metastases. In contrast, all controls presented with disseminated metastases. Both, T-cell and NK-cell dependent mechanisms were involved in the induction of a systemic tumor-protective immunity. Thus, upregulation of IFN- expression in CD8+ T-cells occurred only in those animals that received the mTH-WPRE vaccine, plus the ch14.18-IL-2 boost. Upregulation of this proinflammatory cytokine was not observed in mice immunized with mTH-WPRE vaccine, only. A role for NK-cells was indicated by the complete abrogation of systemic tumor-protective immunity in all animals that were depleted of NK-cells in vivo. Taken together, these data demonstrate that immunization with a post-transcriptionally enhanced DNA vaccine encoding the WPRE sequence combined with a boost of the ch14.18-IL-2 fusion protein completely protects against hepatic metastases in a murine model of neuroblastoma and therefore may lead to a new strategy for immunotherapy and prevention of metastatic neuroblastoma.
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