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Prolonged Maturation and Enhanced Transduction of Dendritic Cells Migrated from Human Skin Explants After In Situ Delivery of CD40-Targeted Adenoviral Vectors¹

Tanja D. de Gruijl^2,*,, Sylvia A. Luykx-de Bakker^2,*,, Bryan W. Tillman^¶, Alfons J. M. van den Eertwegh^*,, Jan Buter^*,, Sinéad M. Lougheed^*,, Gerben J. van der Bij^*,, A. Mahmoud Safer^*,, Hidde J. Haisma^,, David T. Curiel^,,¶, Rik J. Scheper^3,*,, Herbert M. Pinedo and Winald R. Gerritsen^,

Divisions of ^* Immunotherapy and Gene Therapy, Departments of Medical Oncology and Pathology, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands; and ^¶ Division of Human Gene Therapy, Gene Therapy Center, Departments of Medicine, Pathology, and Surgery, University of Alabama, Birmingham, AL 35294

Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumor-associated Ags, critically depends on the in vivo transduction of dendritic cells (DC). Transfection of predominantly nonprofessional APC and only small numbers of DC may hamper proper T cell activation. Aim of this study was, therefore, the targeted, selective, and enhanced in situ transduction of DC. A human skin explant model was used to explore targeted transduction of cutaneous DC after intradermal injection of a bispecific Ab conjugate to link adenoviral (Ad) vectors directly to CD40 on the DC surface. A significantly enhanced transduction efficiency and selectivity, and an increased activation state of migrating DC were thus achieved. Moreover, DC transduced by CD40-targeted Ad maintained their Ag-specific CTL-stimulatory ability for up to 1 wk after the start of migration, in contrast to DC transduced by untargeted Ad, which had lost this capacity by that time. Because DC targeting in vivo might obviate the need for the in vitro culture of autologous DC for adoptive transfer, CD40-targeted Ad vectors constitute a promising new vaccine modality for tumor immunotherapy.

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