Immuno-monitoring of CD8 T cell responses in melanoma patients vaccinated with peptides plus adjuvant, viral vectors, or peptide-pulsed DC

Using the MLPC/tetramer method described last year, we obtained data by pursuing the immunological monitoring of melanoma patients vaccinated with 4 peptides (MAGE-A3, gp100, NA17 and tyrosinase) presented by HLA-A2. We measured responses to these peptides injected with Montanide, but did not know whether the Montanide adjuvant was important for these T cell responses. Indeed, melanoma patients may mount spontaneous responses to these antigenic peptides. We therefore injected the same peptides without adjuvant, and no response was observed. We conclude that Montanide had a clear adjuvant effect for the CD8 T cell responses measured against these four peptides.

Tumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and detection of anti-MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti-MAGE-3.A1 T cells could initiate a tumor regression process.

To understand the role of these T cells, we performed a functional analysis of anti-MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti-MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced IL-10. Transcript profiling confirmed this result and indicated that about 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K and granzyme H, were differentially expressed between the anti-MAGE-3.A1 CTL clones derived from patients vaccinated with peptide-ALVAC or with peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the anti-vaccine CD8 T cells, which may have an impact on their capacity to trigger a tumor rejection response.

This data is extremely relevant for the design and performance of the immunomonitoring of the new clinical trial WP19.

• molecule type
• peptide,
• CD8,
• Major histocompatibility complex class II,
• melanoma antigen MAGE-3,
• granzyme K gene,
• granzyme H gene,
• gp100 antigen,
• CD40 ligand,
• Major histocompatibility complex class I,
• Interleukin-10,
• tyrosinase,
• prostaglandin D2 synthase gene,
• NA17 antigen,
• cloning vector

• organism type
• ALVAC canarypox virus,
• Homo sapiens

• cell type
• T cell,
• dendritic cell,
• cytotoxic T lymphocyte

• experimental design type
• in vivo design experiment

• experimental factor type
• Clinical treatment factor

created over 15 years ago (2 March 2009)    last modified over 13 years ago (28 September 2011)   [ RDF ]   [ RelFinder ]