title: Identification of novel CD33 antigen-specific peptides for the generation of cytotoxic T lymphocytes against acute myeloid leukemia.
abstract: Identification of immunogenic peptides for the generation of cytotoxic T lymphocytes (CTLs) may lead to the development of novel cellular therapies to treat disease relapse in acute myeloid leukemia (AML) patients. The objective of these studies was to evaluate the ability of unique HLA-A2.1-specific nonameric peptides derived from CD33 antigen to generate AML-specific CTLs ex vivo. We present data here on the identification of an immunogeneic HLA-A2.1-specific CD33(65-73) peptide (AIISGDSPV) that was capable of inducing CTLs targeted to AML cells. The CD33-CTLs displayed HLA-A2.1-restricted cytotoxicity against both mononuclear cells from AML patients and the AML cell line. The peptide- as well as AML cell-specificity of CD33-CTLs was demonstrated and the secretion of IFN-gamma by the CTLs was detected in response to CD33(65-73) peptide stimulation. The cultures contained a distinct CD33(65-73) peptide-tetramer(+)/CD8(+) population. Alteration of the native CD33(65-73) peptide at the first amino acid residue from alanine (A) to tyrosine (Y) enhanced the HLA-A2.1 affinity/stability of the modified CD33 peptide (YIISGDSPV) and induced CTLs with increased cytotoxicity against AML cells. These data therefore demonstrate the potential of using immunogenic HLA-A2.1-specific CD33 peptides in developing a cellular immunotherapy for the treatment of AML patients.
authors.affiliation: RUSH University Medical Center, Section of Bone Marrow Transplant and Cell Therapy, 1735 West Harrison Street, Cohn Research Building # 636, Chicago, IL 60612, USA. jbae@rush.edu
authors.forename: Jooeun
authors.initials: J
authors.lastname: Bae
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Martinson
authors.forename: Hans G
authors.initials: HG
authors.lastname: Klingemann
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000276:immunology*; D010455:Peptides / Q000276:immunology* / Q000627:therapeutic use; D063268:Sialic Acid Binding Ig-like Lectin 3; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D015789:HLA-A2 Antigen; D010455:Peptides; D063268:Sialic Acid Binding Ig-like Lectin 3; D007371:Interferon-gamma