T-Cell Responses Directed against Multiple HLA-A0201-Restricted Epitopes Derived from Wilms' Tumor 1 Protein in Patients with Leukemia and Healthy Donors: Identification, Quantification, and Characterization

• Published in: Clinical cancer research 2005-12, Vol.11 (24), p.8799-8807
• Main Authors: REZVANI, Katayoun, BRENCHLEY, Jason M, PRICE, David A, KILICAL, Yasemin, GOSTICK, Emma, SEWELL, Andrew K, JONGMING LI, MIELKE, Stephan, DOUEK, Daniel C, BARRETT, A. John
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antineoplastic agents; Biological and medical sciences; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Hematologic and hematopoietic diseases; Hematologic, other; HLA-A Antigens - immunology; HLA-A2 Antigen; Humans; Immunodominant Epitopes - immunology; Immunodominant Epitopes - pharmacology; immunotherapy; Kidneys; leukemia; Leukemia - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Molecular Sequence Data; Nephrology. Urinary tract diseases; Peptides - immunology; Peptides - pharmacology; Pharmacology. Drug treatments; Tumors of the urinary system; WT1 Proteins - immunology; WT1 Proteins - pharmacology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1314

Purpose: Antigens derived from the Wilms' tumor (WT1) protein, which is overexpressed in leukemias, are attractive targets for immunotherapy. Four HLA-A*0201-restricted WT1-derived epitopes have been identified: WT37, WT126, WT187, and WT235. We determined the natural immunogenecity of these antigens in patients with hematologic malignancies and healthy donor. Experimental Design: To detect very low frequencies of WT1-specific CD8 + T cells, we used quantitative reverse transcription-PCR to measure IFN-γ mRNA production by WT1 peptide–pulsed CD8 + T cells from 12 healthy donors, 8 patients with chronic myelogenous leukemia, 6 patients with acute myelogenous leukemia, and 8 patients with acute lymphoblastic leukemia. Results: Responses were detected in 5 of 8 chronic myelogenous leukemia patients, 4 of 6 patients with acute myelogenous leukemia, and 7 of 12 healthy donors. No responses were detected in patients with acute lymphoblastic leukemia. The magnitude and extent of these CD8 + T-cell responses was greater in patients with myeloid leukemias than in healthy donors. Clonotypic analysis of WT1-specific CD8 + T cells directly ex vivo in one case showed that this naturally occurring population was oligoclonal. Using fluorescent peptide-MHC class I tetramers incorporating mutations in the α3 domain (D227K/T228A) that abrogate binding to the CD8 coreceptor, we were able to confirm the presence of high-avidity T-cell clones within the antigen-specific repertoire. Conclusion: The natural occurrence of high-avidity WT1-specific CD8 + T cells in the periphery could facilitate vaccination strategies to expand immune responses against myeloid leukemias.