Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
will direct antigen to various intracellular compartments or sequences coding for
immunomodulatory molecules can be added to these vaccines. The main limitation of this
approach is the inefficiency of the vaccine delivery method. Intramuscular injections such as
those optimized for DNA vaccine delivery in mice did not show the same efficiency in
humans, perhaps due to the different volume used for injection. Viral vectors have been tested
for their efficiency as DNA vaccine delivery systems with better success, but reactivity
against the vector itself limited their efficacy overall. An electroporation method seems
promising thus far, as it has been shown to enhance antigen expression upon intramuscular
injection (Ahlen et al., 2007).
Despite similar limitations concerning their delivery, RNA vaccines have also been tested. It
was observed that mRNA injection into the muscle induces protein expression in mice (Wolff
et al., 1990). Additionally, it was demonstrated that intradermal injection of antigen-encoding
RNA, together with an adjuvant, had a positive impact on the anti-tumor immune response
(Weide et al., 2009). In order to optimize injection procedures, stabilization of RNA with
protamine has been used to protect the molecule from RNases and promote persistence.
Similar to DNA transfection, following mRNA injection, transfected cells are engulfed by
DCs that cross-present antigen, unless the DCs themselves were directly transfected.
Interestingly, Fotin-Mleczek and colleagues combined the same mRNAs in two different
forms to induce a potent immune response in a mouse model of tumor vaccination: a non-
complexed free RNA known to have a high translation efficiency and a stabilized protamine-
complexed mRNA, which stimulated TLR7 (Fotin-Mleczek et al., 2011). This combination
triggered a humoral and cellular response and allowed the immune system to mount a
response despite the tumor-induced immune suppression.
3) Cell-based vaccines
Cellular vaccines have also been developed in the context of cancer immunotherapy. The
overall aim of cancer vaccines is to induce an anti-tumor CD8 + T cell response against the
TAAs. Several cell-based strategies have been tested to achieve that goal, including using the
tumor cells directly as a source of antigen, or injecting DCs that have been previously loaded
with the tumor antigen of interest. Additionally, other cell types have been examined for their
feasibility as antigen delivery vehicles.
(a) Whole tumor-cell vaccines
The main benefit of using tumor cells as a source of antigen is that it does not require detailed
prior knowledge of the immunodominant antigen responsible for promoting a protective
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