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

tel-00827710, version 1 - 29 May 2013
1) Peptide and protein-based vaccines
Tumor-associated antigens (TAA) are proteins that are only expressed by or expressed at a
much higher level by tumor cells. Since the identification and cloning of the first human TAA
gene, peptide vaccination has been considered a promising approach for cancer treatment. The
first studies were performed with peptides 8 to 10 aminoacids in length that would bind
directly to MHC molecules without the requirement for endocytosis and/or intracellular
processing. Aichele et al. initially demonstrated that injection of a peptide encoded by LCMV
elicited a robust anti-viral T cell response in mice (Aichele et al., 1990). However, later data
demonstrated that injection of short peptides induced tolerance rather than immunity (Toes et
al., 1996). This approach clearly did not give the robust T cell response against antigen that
had been expected. Further characterization of the response to injected peptides revealed that
those peptides that elicited efficient responses actually contained overlapping epitopes for
cytotoxic and helper T cells (Fayolle et al., 1991).
Based on these data, longer peptides, physically linking several epitopes (CTL as well as T-
helper epitopes) were then developed (Perez et al., 2010). Injection of these chimeric peptides
displays several advantages as compared to the previous short peptide injection strategy. Due
to their length, they cannot directly bind MHC molecules and, therefore, must be engulfed
and processed prior to presentation. This implies that the long peptides are taken up by
professional APCs, which would limit presentation on MHC-I expressed by non-specialized
APCs known to trigger short cytotoxic T cell response or even tolerance, which could explain
the inefficiency of the short peptide model. Moreover, the requirement for engulfment and
processing inside APCs allows a longer period of antigen persistence (Melief and van der
Burg, 2008). The presence of several epitopes in the same vaccine permits activation of
antigen-specific CD4 + and CD8 + T cells concurrently, and limits the phenomenon of tumor
escape. Experimental mouse models and clinical studies using either naturally linked
epitopes, or artificially linked epitopes have given promising results (Shirai et al., 1994; Zeng
et al., 2002).
54