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

tel-00827710, version 1 - 29 May 2013
have a boosting effect, due to the desensitization of certain cell types to IFNα (Francois-
Newton et al., 2011). This desensitization may explain why imiquimod did not improve the
efficiency of the vaccine during the trial period.
4) Combination of several approaches: example of cancer treatments
In the previous section we discussed the combination between antigen and adjuvant as a
single therapy. Now we will consider the combination between more than two different
reagents as they may be combined and used in the treatment of cancer. Several approaches
have been developed in order to further understand the mechanisms of tumor growth, the anti-
tumor response and the development of therapies to enhance tumor clearance. First, the tumor
can be targeted, either for killing or for modifications that might render it more immunogenic.
Secondly, the immune system could be boosted against specific TAAs in order to obtain an
efficient response even if the initial stimulation by tumor antigens was suboptimal. Finally,
the immunosuppressive environment created by the tumor could be altered such that the
development of an effective inflammatory response was allowed (Lesterhuis et al., 2011).
(a) Treatments targeting directly tumor cells
Initial chemotherapy treatments targeting tumors involved the use of broadly acting
compounds that induced the rapid death of dividing cells. With time, the signaling pathways
involved in cell survival and tumor growth were identified and more specific agents blocking
unique steps in these pathways were developed to stop tumor progression and promote tumor
cell death. This approach was minimally successful, demonstrating some progress in inducing
tumor regression, but resistance mechanisms often developed and the treatment benefits did
not extend to long-term survival (Vanneman and Dranoff, 2012). However, these treatments
are interesting for further study because they induced death in at least a fraction of tumor
cells, facilitating the effect of cytotoxic T cells. These types of treatments also trigger the
release of dying cell debris and danger signals that can be taken up by DCs, such as ATP or
HMGB1 that will result in immune cell activation.
(b) Development of an efficient anti-tumor immune response
Another approach to fight cancer is to boost the immune response in order to render it more
efficient against specific tumor antigens. As discussed previously, different types of antigen
can be used for vaccination (Table 5). The aim is to use a more immunogenic antigen in order
to mount an effective T cell response directed against tumor. Drugs modulating the steps of
immune response could be combined with the vaccine treatment to obtain the most efficient T
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