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

tel-00827710, version 1 - 29 May 2013
compared to other APC populations. Moreover, DCs also express high levels of costimulatory
molecules and immunostimulatory cytokines upon activation that are required for an effective
T cell response. Consequently many trials have been performed to investigate the capability
of these cells to mount an anti-tumor immune response when given as a vaccine. Together,
these studies have demonstrated that DCs pulsed with tumor antigens can induce a protective
immunity in mouse models (Fuertes et al., 2011), and clinical trials are currently ongoing to
evaluate the feasibility of multiple DC-based vaccines in humans (Palucka and Banchereau,
2012).
The first human DC-based vaccine trials were performed using cDCs that have been isolated
or expanded ex vivo and then loaded with the antigen of interest. DCs can either be loaded
with the specific peptide or the protein, or they can be transfected with the nucleic acid
encoding the specific epitope for presentation (Palucka et al., 2005). The prostate cancer DC-
based vaccine, sipuleucel-T, is the only DC-based vaccine that has received the approval of
the FDA. Sipuleucel-T is composed of autologous mononuclear cells cultured with a fusion
protein containing a common prostate cancer antigen, the prostatic acid phosphatase (PAP),
linked to GM-CSF (Higano et al., 2009). The main limitation of this approach is that the
sequence of the antigen and the epitope must be well defined. Another approach without this
caveat is to load DCs with dying cells or tumor lysates in order to promote an anti-tumor
response based on the processing and presentation of unknown tumor antigens. In this case,
the immunodominant epitope(s) is/are likely present but does not require detailed knowledge
on the part of the investigator (Palucka et al., 2006).
There are, however, limitations with this approach as well. First, the majority of DCs injected
remains at the injection site upon administration and fail to migrate to the lymph node. This
sequestration could result in DC dedifferentiation due to extended time in the injected site
tissue microenvironment; a potential consequence of this is the induction of immune tolerance
by these cells, rather than activation. Second, there is a concern that DCs are terminally
differentiated cells. Consequently, they cannot be expanded to large numbers ex vivo and the
life span of these cells upon injection is only about 24-48 hours. This limited time frame
results in poor antigen delivery to the lymphoid tissue, where optimal T cell priming occurs.
Several studies have been performed to address and, hopefully, circumvent these potential
problems using strategies such as using different routes of vaccination and, in particular, the
use of intranodal injection (Aarntzen et al., 2008). Multiple observations made during these
studies have allowed for the optimization of DC-based vaccine development. It has been
shown that upon uptake, the antigen must be transferred to endogenous DCs in order for the
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