Xinsheng Liao1 1, *, Yongqing Li 1, *, Chiara
Bonini 1, Smita Nair 2, Eli Gilboa 2,
Philip D. Greenberg 1, and
Cassian Yee 1, @
1 Division of Clinical Research, Fred Hutchinson Cancer
Research Center, 1100 N. Fairview Avenue, Seattle, WA 98109, USA
2 Center for Genetic and Cellular Therapies, Department
of Surgery, Duke University Medical Center, Durham, NC 27710, USA
@ Corresponding author. To whom correspondence and reprint
requests should be addressed.
E-mail: cyee@fhcrc.org
Common tumor vaccination strategies utilizing peptide-pulsed dendritic
cells (DC) are limited to targeting antigens with known epitopes in patients
expressing a defined restricting allele and can result in the preferential
induction of low-avidity T cells that fail to recognize tumor cells. The
use of dendritic cells transfected with RNA encoding tumor antigen offers
the prospect of antigen-specific immunization without requiring prior knowledge
of the immunogenic epitope or restricting allele, since epitopes from the
translated protein are processed by the endogenous antigen-presentation
machinery. However, its use in vaccine studies has been limited by low
RNA transfection efficiency and the use of immature DC as recipient cells.
In this study, we report an RNA transfection strategy that routinely achieves
expression in 40–50% of mature DC, which are better stimulator cells. Such
RNA-transfected mature DC exhibited a prolonged duration of presentation
of immunogenic epitopes compared to peptide-pulsed DC, induced greater
frequencies of tumor antigen-specific CTL, and generated a CTL population
that exhibited higher target avidity and increased tumor lytic capacity.
These studies provide compelling in vitro data supporting the evaluation
of RNA-transfected mature DC in vaccination protocols as a means to overcome
several obstacles to generating anti-tumor responses in vivo.
Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.ymthe.2004.02.011.
1. Coughlin CM, Vance BA, Grupp SA, and Vonderheide RH, "RNA-transfected CD40-activated B cells induce functional T cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy".
2. Santulli-Marotto S, Nair SK, Rusconi C, Sullenger B, and Gilboa E, "Multivalent RNA Aptamers That Inhibit CTLA-4 and Enhance Tumor Immunity".
3. Kern DH, Chow N, and Pilch YH, "Lymphocyte Populations Participating in Cellular Antitumor Immune Responses Mediated by Immune RNA", J. Natl. Cancer Inst. 60, 335-344 (1978).
4. Frenster JH, "Phytohemagglutinin-Activated Autochthonous Lymphocytes for Systemic Immunotherapy of Human Neoplasms", Annals of the New York Academy of Science, vol. 277: pp. 45-51 (1976).
5. DeCarvalho S, "Effect of RNA from Normal Human Marrow on Leukaemic Marrow In-Vivo", Nature, vol. 197, no. 4872, pp. 1077-1080, (March 16, 1963).
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