Artikel
Development of a GBM vaccine based on HLA-A2-associated peptides
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Veröffentlicht: | 4. Juni 2012 |
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Gliederung
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Objective: Cancer vaccines are an attractive alternative to standard cancer treatments and are already being tested in humans. Ideally, T-cell-mediated tumor immunotherapy is directed against several tumor-associated antigens in order to circumvent the so called 'immune escape'.
Methods: To identify suitable peptides for vaccination therapy 32 HLA A2-positive GBM samples were submitted to peptide elution from MHC/peptide complexes using HPLC/MS, and the isolated peptides were sequenced followed by a comparative mRNA expression analysis of the same GBM samples and normal brain as well as non-CNS normal tissues. Expression of selected proteins was tested by immunohistochemistry using a tissue microarray including biopsies of 221 GBM and 29 recurrent tumors. In vitro immunogenicity of selected peptides was tested by using PBMCs of healthy individuals and GBM patients.
Results: More than three thousand A2-restricted peptides were isolated and analyzed according to comparative expression in GBM vs. normal brain and non-CNS tissues, resulting in the selection of 10 glioma-associated antigens. Interestingly, the set of peptides identified did not overlap with previously described glioma antigens. Importantly, there was no tolerance to the glioma antigens in GBM patients corroborating the relevance of the selected peptides. Finally, expression analysis in a large set of tumors revealed that corresponding proteins were present in 75–100% of primary and recurrent GBM analyzed. However, frequency of antigen-expressing tumor cells varied markedly with a mean of 14–88% positive cells which further supports the need that an effective anti-GBM vaccine should be directed against several tumor-associated proteins to target as many tumor cells as possible.
Conclusions: The originality and power of this approach has allowed to fill a gap in the field of glioma immunotherapy by identifying novel glioma-associated antigens. The antigens we have isolated meet the criteria of overexpression in tumor samples versus normal tissues and were incorporated into the multipeptide vaccine IMA950 which will now be tested for the treatment of GBM and recurrent GBM in three independent clinical phase I trials.