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

tel-00827710, version 1 - 29 May 2013
and inhibitory drugs to limit immunosuppressive conditions in tumor microenvironment. Each
of these strategies individually revealed only a limited efficiency, but promising results were
obtained when several of them were given in combination (Dougan et al., 2010, Balachandran
et al., 2011, Hodi et al., 2008). Interactions between the different approaches should be
studied further to determine the best strategy(ies) to treat cancer. Bioavailability of the
different molecules or vaccines, step of the immune response that is targeted and tumor
growth, are all factors that should be taken into consideration to determine the optimal dose,
sequence and timing for the application of the different treatment strategies.
(i) Multiple effects of a given reagent
Each of these strategies was developed to target one single element of the tumor development.
Often side effects are observed and also must be considered when treatment combinations are
planned. The response to a given vaccine may involve the contribution of unknown
mechanims that could be modified by a second therapy given concurrently. As we observed in
our model, a given cytokine, type I IFN, has pleiotropic roles on both immune and non-
immune cells; a given adjuvant, poly I:C, is responsible for its direct effect through TLR and
RLR engagement but also provides a second wave of activation through type I IFN (Figures
52 and 54). Interestingly, molecules developed to target signaling pathways implicated in
tumor survival and growth have been demonstrated to also be involved in the activation and
differentiation of immune cells (Vanneman and Dranoff, 2012). For example, cetuximab is an
anti-tumor agent composed of neutralizing antibodies directed against the EGF receptor. It
blocks the growth signaling pathway in tumor cells; however it has also been demonstrated to
facilitate the uptake of tumor cells by inducing the formation of immune complexes (Correale
et al., 2012). IAP inhibitors that sensitize tumor cells to apoptosis actually enhance T and NK
cell function (Fesik, 2005; Dougan et al., 2010). This dual activity illustrates the need for an
in-depth understanding of the various actions of a given molecule on tumor cells, but also in
the context of the immune response, such that optimal administration conditions can be
determined and potential combinatorial side effects can be identified and predicted.
(ii) Opposite effects of reagents depending on the timing
of administration
We observed in our model that early delivery of poly I:C inhibited subsequent priming while,
if delivered a few days later, it boosted the same response (Figure 37). The same functionally
opposing effects have been observed for other molecules depending on the timing of
administration. Sunitinib is an inhibitor of tyrosine kinase receptors such as VEGF or PDGF
receptors and this inhibition results in limiting tumor growth. Moreover it also acts on
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