Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant

• Published in: Leukemia Vol. 27; no. 7; pp. 1538 - 1547
• Main Authors: Weber, G, Gerdemann, U, Caruana, I, Savoldo, B, Hensel, N F, Rabin, K R, Shpall, E J, Melenhorst, J J, Leen, A M, Barrett, A J, Bollard, C M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2013; Nature Publishing Group
• Subjects: 692/699/249/1529; 692/700/565/2319; 692/700/565/251; 692/700/565/545/576/1955; Adoptive immunotherapy; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Cancer Research; Care and treatment; Cell Line; Critical Care Medicine; Cytotoxicity; Dendritic Cells - cytology; Dendritic Cells - immunology; Elastase; Enzyme-linked immunosorbent assay; Epitope Mapping; Gene therapy; Graft versus host reaction; Graft vs Leukemia Effect - immunology; Graft-versus-leukemia reaction; Hematology; Hematopoietic Stem Cell Transplantation - methods; Histocompatibility antigen HLA; Histocompatibility Testing; Humans; Immunogenicity; Immunophenotyping; Immunotherapy; Intensive; Interferon; Internal Medicine; Leukemia; Leukemia, Myeloid - immunology; Leukemia, Myeloid - therapy; Leukocyte Elastase - immunology; Leukocytes; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Medical schools; Medicine; Medicine & Public Health; Melanoma; Melanoma-associated antigen; Membrane Glycoproteins - immunology; Myeloblastin - immunology; Myeloid leukemia; Neutrophils; Oncology; original-article; Patient outcomes; Pattern recognition; Peptide Fragments - immunology; Peptide libraries; Peptides; Peripheral blood; Physiological aspects; Proteinase; Proteinase 3; Proteins; Recurrence; Remission (Medicine); Stem cell transplantation; Stem cells; T cells; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; Tissue Donors; Transplantation; Transplantation, Homologous; Transplants & implants; Tumors; Vaccines; WT1 Proteins - immunology; γ-Interferon; United States > US; tumor-associated antigens; myeloid leukemia; cytotoxic T cells; stem cell transplantation; immunotherapy; graft-versus-leukemia effect
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.66

Adoptive immunotherapy with
ex vivo
expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines.
In vitro
experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type.