Abstracts (complete list) - Wissenschaft Online

Stephan Schierer, Andrea Hesse, Ina Mueller, Eckhart Kaempgen, David T. Curiel,
Gerold Schuler, Alexander Steinkasserer, Dirk M. Nettelbeck
Modulation of viability and maturation of human monocytederived
dentritic cells by oncolytic adenoviruses
In spite of intensive efforts to modify oncolytic adenovirus (ads) for improved specificity
and efficacy of cancer cell lysis, it is becoming increasingly clear that the killing of noninfected
cancer cells in parallel to viral cell lysis will be crucial for oncolytic ads to be
effective in the clinic. An attractive scenario towards this goal is the induction of
systemic anti-tumor immunity by adenoviral oncolysis. In order to establish the basis
for the development of adenoviral oncolytic vaccination we examined the effects of
oncolytic ads on the biology of human dendritic cells (DCs). DCs are the most potent
antigen presenting cells, key regulators of immune induction and have been intensively
exploited for various vaccination protocols. The prime objective of this study was to
investigate how optimized, melanoma-targeted oncolytic ads affect the viability and
maturation of human monocyte-derived DC and the potency of such DCs to activate T
cells.
Both immature DCs (iDCs) and mature DCs (mDCs) were transducible with luciferase
encoding ads at high titers. Fiber chimeric ads with an ad serotype 3 derived knob
domain (5/3fiber) showed an improved transduction efficacy compared with an ad with
serotype 5 (5fiber) fiber. After infection of iDC and mDC with oncolytic ads (5 or
5/3fiber) at high titers (5000vp/cell), no significant toxicity was observed. Oncolytic ads
showed no or strongly attenuated DNA replication in human DCs, thus confirming their
replication specificity. As determined by staining of cell surface maturation markers of
DCs two to three days post infection with oncolytic ads (5 or 5/3fiber), we observed,
dependent on the donor, no or a partial DC maturation. With respect to the maturability
of DCs with cytokines and/or LPS, no negative influence of infection with oncolytic
adenovirus was documented. However, we did find an increase in the IL-12 secretion of
LPS resp. LPS/IFNg matured DCs after infection with oncolytic ads. Finally DCs, infected
with oncolytic ads for 3 days, matured and then loaded with peptide were still able to
prime and stimulate specifically CD-8 T-cells with similar or superior efficacy compared
to uninfected DCs, dependent on the donor.
In conclusion, oncolytic ads do not harm viability and maturability of monocyte derived
DCs, but also do not induce complete maturation of these cells. Therefore, oncolytic ads
might represent a promising tool for oncolysis-induced anti-tumor immune activation,
however, this strategy might require additional maturation signals for DCs, for example
by expression of immunostimulatory genes inserted into the genome of oncolytic ads.