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FLT3 Ligand Enhances the Cancer Therapeutic Potency of Naked RNA Vaccines

Kreiter, Sebastian, Diken, Mustafa, Selmi, Abderraouf, Diekmann, Jan, Attig, Sebastian, Hüsemann, Yves, Koslowski, Michael, Huber, Christoph, Türeci, Özlem, Sahin, Ugur·2011·Cancer Research
DOI 10.1158/0008-5472.can-11-0291

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Abstract

Intranodal immunization with antigen-encoding naked RNA may offer a simple and safe approach to induce antitumor immunity. RNA taken up by nodal dendritic cells (DC) coactivates toll-like receptor (TLR) signaling that will prime and expand antigen-specific T cells. In this study, we show that RNA vaccination can be optimized by coadministration of the DC-activating Fms-like tyrosine kinase 3 (FLT3) ligand as an effective adjuvant. Systemic administration of FLT3 ligand prior to immunization enhanced priming and expansion of antigen-specific CD8+ T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodal RNA. Unexpectedly, plasmacytoid DCs (pDC) were found to be essential for the adjuvant effect of FLT3 ligand and they were systemically expanded together with conventional DCs after treatment. In response to FLT3 ligand, pDCs maintained an immature phenotype, internalized RNA, and presented the RNA-encoded antigen for efficient induction of antigen-specific CD8+ T-cell responses. Coadministration of FLT3 ligand with RNA vaccination achieved remarkable cure rates and survival of mice with advanced melanoma. Our findings show how to improve the simple and safe strategy offered by RNA vaccines for cancer immunotherapy. Cancer Res; 71(19); 6132–42. ©2011 AACR.

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Metadata

Authors
Kreiter, S., Diken, M., Selmi, A., Diekmann, J., Attig, S., Hüsemann, Y., Koslowski, M., Huber, C., Türeci, Ö., & Sahin, U.
Affiliations
Authors' Affiliations: 1Institute for Translational Oncology and Immunology (TRON); 2Department of Internal Medicine III, Division of Translational and Experimental Oncology, Johannes Gutenberg University; 3Ribological, Biontech AG; and 4Ganymed Pharmaceuticals AG, Mainz, Germany
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-09-29
Volume
71
Issue
19
Pages
6132-6142
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-11-0291
Cited by
75
References
7
Language
en

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