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

tel-00827710, version 1 - 29 May 2013
immune response. Moreover, using entire tumor cells will allow for multiple epitopes to be
processed and presented, in the hope that a broadly reactive response will be increasingly
protective. When tested, the vaccine has been comprised of autologous cells originating from
a resected fragment of the patient’s own tumor. For example, M-Vax is composed of
autologous irradiated tumor cells that have been modified with a hapten (dinitrophenyl) in
order to improve its immunogenicity, and then mixed with BCG as an adjuvant. This vaccine
has been tested intradermally for the treatment of melanoma (Berd, 2004). A limitation of this
vaccine strategy is the difficulty in obtaining sufficient numbers of cells for vaccination.
Another well-characterized approach is the use of the allogeneic whole cell vaccines. These
are cellular “cocktails” composed of several cancer cell lines mixed together. One advantage
is that logistically, it is far easier to generate a mix of cell lines as compared to extracting
autologous tumor cells for a vaccine. Furthermore, the different cell lines can be generated
from different stages of tumor growth and development, thus representing a broader antigenic
profile. This is an important point to consider as the antigenic repertoire of a tumor evolves
over time, especially when metastases appear: the mixing of different cell lines increases the
variety of TAAs exposed to the immune system and, in this way, can counteract immune
escape. In particular, the melanoma vaccine compound Melacine is made of lyophilized
melanoma lysates from two melanoma cell lines mixed with a complex adjuvant (Detox PC)
(Sondak and Sosman, 2003). Similarly, the prostate treatment vaccine Onyvax-P is composed
of three irradiated prostate cancer cell lines, which are administered with BCG intradermally
to increase immune control in prostate cancer patients (Schlom et al., 2007).
While this kind of vaccines appears promising from a theoretical standpoint, the success of
these therapies remains limited thus far. One explanation is that tumor-associated antigens are
usually only weakly antigenic and more often they induce tolerance rather than immunity.
Several directions must be explored in order to improve their efficiency; in particular the
choice of adjuvant used to overcome immune suppression often observed in cancer patients
(Copier and Dalgleish, 2010). Additionally, as the precise antigens are not known in this
context, it is difficult to study their efficiency specifically. Thus an overall better
understanding of immune response induced by these vaccines and the discovery of novel
biomarkers helping to define their efficiency is greatly needed.
(b) DC-based vaccines
To elicit the most efficient response, a cancer vaccine will have to deliver the antigen to the
lymphoid tissue in an immunostimulatory context. As described previously, DCs are known
to be the most potent APC with an increased ability to present and cross-present antigen as
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