Abstract
Background
The transcription factor, WT1, is highly overexpressed in malignant pleural mesothelioma (MPM) and immunohistochemical stains for WT1 are used routinely to aid in its diagnosis. Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1 vaccine comprised of four class I and class II peptides in patients with thoracic neoplasms expressing WT1.
Methods
Therapy consisted of six subcutaneous vaccinations administered with Montanide adjuvant on weeks 0, 4, 6, 8, 10, and 12, with 6 additional monthly injections for responding patients. Injection sites were pre-stimulated with GM-CSF (70 mcg). Immune responses were evaluated by DTH, CD4 T-cell proliferation, CD8 T-cell interferon gamma release, intracellular cytokine staining, WT1 peptide MHC-tetramer staining, and cytotoxicity against WT1 positive tumor cells.
Results
Nine patients with MPM and 3 with NSCLC were vaccinated, with 8 patients receiving at least 6 vaccinations; in total, 10 patients were evaluable for immune response. Six out of nine patients tested demonstrated CD4 T-cell proliferation to WT1 specific peptides, and five of the six HLA-A0201 patients tested mounted a CD8 T-cell response. Stimulated T cells were capable of cytotoxicity against WT-1 positive cells. Vaccination also induced polyfunctional CD8 T cell responses.
Conclusions
This multivalent WT1 peptide analog vaccine induces immune responses in a high proportion of patients with thoracic malignancies with minimal toxicity. A randomized trial testing this vaccine as adjuvant therapy in MPM is planned.
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Acknowledgments
We thank Dr. Bo Dupont and Alice Yeh at Memorial Sloan-Kettering Cancer Center for HLA genotyping and Dr. M. Roederer for providing the SPICE software. This study was supported by NIH PO1 23766, Innovive Pharmaceuticals, the Mesothelioma Applied Research Foundation, Tudor and Glades Funds and the Experimental Therapeutics Center of MSKCC.
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Krug, L.M., Dao, T., Brown, A.B. et al. WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. Cancer Immunol Immunother 59, 1467–1479 (2010). https://doi.org/10.1007/s00262-010-0871-8
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DOI: https://doi.org/10.1007/s00262-010-0871-8