title: Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia.
abstract: The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed in many hematologic malignancies, including chronic myeloid leukemia (CML). The sensitivity of CML to donor lymphocyte infusion after allogeneic stem cell transplantation suggests this tumor can be highly susceptible to cellular immunotherapy targeted to tumor associated antigens. We therefore tested whether functional PRAME-specific cytotoxic T lymphocytes (PRAME CTLs) could be generated and expanded from healthy donors and CML patients, or whether the limited immunogenicity of this CTA coupled with tumor-associated anergy would preclude this approach. Using optimized culture conditions and HLA-A*02-restricted PRAME-peptides, we have consistently generated PRAME CTLs from 8/9 healthy donors and 5/6 CML patients. These CTLs released IFNgamma in response to PRAME peptides (between 113 +/- 8 and 795 +/- 23 spot forming cells/10(5) T cells) and lysed PRAME peptide-loaded cells (45 +/- 19% at an effector:target [E:T] ratio of 20:1) in a MHC-restricted fashion. Importantly, these CTLs recognized and had cytotoxic activity against HLA-A*02(+)/PRAME(+) tumor cell lines, and could recognize and respond to primary CML cells. PRAME CTLs were generated almost exclusively from the naive T-cell compartment, and clonal analysis showed these cells could have high alphabetaTCR-peptide avidity. PRAME CTLs or vaccines may thus be of value for patients with CML.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Concetta
authors.initials: C
authors.lastname: Quintarelli
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Biagio
authors.initials: B
authors.lastname: De Angelis
authors.forename: Valentina
authors.initials: V
authors.lastname: Hoyos
authors.forename: Martha
authors.initials: M
authors.lastname: Mims
authors.forename: Luigia
authors.initials: L
authors.lastname: Luciano
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; C404944:PRAME protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D007371:Interferon-gamma