WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer Journal Article

   

Authors:	Krug, L. M.; Dao, T.; Brown, A. B.; Maslak, P.; Travis, W.; Bekele, S.; Korontsvit, T.; Zakhaleva, V.; Wolchok, J.; Yuan, J.; Li, H.; Tyson, L.; Scheinberg, D. A.
Article Title:	WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer
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. © 2010 Springer-Verlag.
Keywords:	immunohistochemistry; adult; clinical article; controlled study; human tissue; aged; aged, 80 and over; middle aged; unclassified drug; human cell; drug efficacy; drug safety; treatment duration; adjuvant therapy; outcome assessment; neoplasm staging; cd8+ t lymphocyte; lymphocyte proliferation; cd8-positive t-lymphocytes; kidney disease; lung disease; lung non small cell cancer; carcinoma, non-small-cell lung; granulocyte macrophage colony stimulating factor; cell line; antineoplastic activity; drug structure; drug specificity; injection site reaction; immune response; amino acid sequence; molecular sequence data; immunotherapy; gamma interferon; cancer vaccine; cancer vaccines; immunogenicity; montanide isa 51; cancer immunization; cd4+ t lymphocyte; cd4-positive t-lymphocytes; peptide fragments; mesothelioma; peptide vaccine; cytokine release; hla a antigen; non-small cell lung cancer; injection site erythema; vaccine; hematologic disease; wt1; wt1 proteins; wt1 peptide vaccine; injection site pruritus; injection site swelling
Journal Title:	Cancer Immunology, Immunotherapy
Volume:	59
Issue:	10
ISSN:	0340-7004
Publisher:	Springer
Date Published:	2010-01-01
Start Page:	1467
End Page:	1479
Language:	English
DOI:	10.1007/s00262-010-0871-8
PUBMED:	20532500
PROVIDER:	scopus
PMCID:	PMC4004362
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-77955553483&partnerID=40&md5=26626edd52795221700d5ef61c7d4700
Notes:	--- - "Export Date: 20 April 2011" - "CODEN: CIIMD" - "Source: Scopus"

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