1. Immune responses to cancer vaccine antigens
To understand why a minority of cancer patients vaccinated with defined tumor antigens display an objective tumor regression while most of them do not, it is essential to know whether and how the anti-tumor immune responses of the patients are either primed, amplified, or modified by the vaccinations. Our initial work suggested that in most vaccinated patients, even in those who displayed tumor regression, it was difficult to ascertain the existence of an anti-vaccine T cell response. We nevertheless felt that it was crucial to know whether or not low-level responses had occurred and whether such cytolytic T lymphocytes (CTL) responses showed a correlation with tumor regression, in order to understand why most patients failed to show any evidence of regression. We therefore developed a sensitive approach based on in vitro restimulation of blood lymphocytes with the antigenic peptide over two weeks, followed by labeling with tetramers. To evaluate precursor frequencies, these mixed lymphocyte-peptide cultures were conducted under limiting dilution conditions. Cells that were labeled with the tetramer were cloned, the lytic specificity of the clones was verified, and their diversity was analyzed by T cell receptor (TCR) sequencing (Coulie 2001; Karanikas 2003).
Working with patients vaccinated either with Dr J.-F. Baurain at the University hospital or by Dr N. Van Baren at the Ludwig Institute, we focused on the analysis of CD8 T cell responses to antigenic peptides presented by HLA-A1 or A2 molecules.
A first result that we obtained thanks to our methodological approach to this immunomonitoring is the surprisingly low levels of anti-vaccine T cell responses found in several of the patients who displayed tumor regression after the vaccinations. It is still unclear whether the induction by new vaccination modalities of much higher frequencies of blood anti-vaccine T cells would lead to more tumor regressions. However, clinical studies with more immunogenic vaccines, such as those including dendritic cells, have not yet demonstrated a superior clinical efficacy.
Ongoing clinical studies are conducted with a combination of 8 different antigenic peptides, administered alone or with immunological adjuvants such as the oligonucleotides CpG7909, a TCR9 ligand, or Montanide ISA51, a clinical grade incomplete Freund’s adjuvant. Monitoring the frequencies of blood T cells against such individual peptide indicates an effect of the adjuvants, with no clear hierarchy between the two, and clear differences between the immunogenicities of the different peptides.
But we so far failed to observe a correlation between the intensities or breadth (proportions of peptides against which a response is observed) of the immune reponses and the clinical impact of the vaccinations. All these results suggest that the main limitation to the clinical efficacy of these therapeutic anti-cancer vaccines is not the intensity of the induced anti-vaccine T cell responses.
To know more... (pdf chapter of the last de Duve Institute report)
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