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In vitro Stimulation with WT1 Peptide-Loaded Epstein-Barr Virus-Positive B Cells Elicits High Frequencies of WT1 Peptide-Specific T Cells with In vitro and In vivo Tumoricidal Activity

¹ Bone Marrow Transplantation Service, ² Department of Pediatrics, ³ Adoptive Immune Cell Therapy Laboratory, ⁴ Department of Neurology, ⁵ Infectious Diseases Service, ⁶ Department of Epidemiology and Biostatistics, ⁷ Department of Developmental Hematology, and ⁸ Immunology Department, Memorial Sloan-Kettering Cancer Center, New York, New York

The Wilms tumor protein (WT1) is overexpressed in most acute and chronic leukemias. To develop a practicable, clinically applicable approach for generation of WT1-specific T cells and to comparatively evaluate the immunogenicity of WT1 in normal individuals, we sensitized T cells from 13 HLA-A0201⁺ and 5 HLA-A2402⁺ donors with autologous EBV-transformed B cells or cytokine-activated monocytes, loaded with the HLA-A0201-binding WT1 peptides _126–134RMFPNAPYL or _187–195SLGEQQYSV or a newly identified HLA-A2402-binding WT1 peptide _301–310RVPGVAPTL. WT1-specific T cells were regularly generated from each donor. T cells sensitized with peptide-loaded EBV-transformed B cells generated higher numbers of WT1-specific T cells than peptide-loaded cytokine-activated monocytes. Contrary to expectations, the frequencies of WT1 peptide-specific T cells were equivalent to those generated against individual highly immunogenic HLA-A0201-binding EBV peptides. Each of these T-cell lines specifically killed WT1⁺ leukemias and solid tumors in an HLA-restricted manner but did not lyse autologous or HLA-matched normal CD34⁺ hematopoietic progenitor cells or reduce their yield of colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), or mixed colonies (CFU-mix). Furthermore, WT1 peptide-specific T cells after adoptive transfer into nonobese diabetic-severe combined immunodeficient mice bearing subcutaneous xenografts of WT1⁺ and WT1^– HLA-A0201⁺ leukemias preferentially accumulated in and induced regressions of WT1⁺ leukemias that expressed the restricting HLA allele. Such cells are clinically applicable and may prove useful for adoptive cell therapy of WT1⁺ malignant diseases in humans.

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