Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies.
Cell-based immunotherapy in settings of allogeneic stem cell transplantation or donor leukocyte infusion has curative potential, especially in hematologic malignancies. However, this approach is severely restricted due to graft-versus-host disease (GvHD). This limitation may be overcome if target antigens are molecularly defined and effector cells are specifically selected. We chose formin-related protein in leukocytes 1 (FMNL1) as a target antigen after intensive investigation of its expression profile at the mRNA and protein levels. Here, we confirm restricted expression in peripheral blood mononuclear cells (PBMCs) from healthy donors but also observe overexpression in different leukemias and aberrant expression in transformed cell lines derived from solid tumors. We isolated allorestricted T-cell clones expressing a single defined TCR recognizing a particular HLA-A2-presented peptide derived from FMNL1. This T-cell clone showed potent antitumor activity against lymphoma and renal cell carcinoma cell lines, Epstein-Barr virus (EBV)-transformed B cells, and primary tumor samples derived from patients with chronic lymphocytic leukemia (CLL), whereas nontransformed cells with the exception of activated B cells were only marginally recognized. Allorestricted TCRs with specificity for naturally presented FMNL1-derived epitopes may represent promising reagents for the development of adoptive therapies in lymphoma and other malignant diseases.
Schuster
Ingrid G
IG
Institute of Molecular Immunology, Forschungszeutrum für Umwelt und Gesundheit (GSF)-National Research Center for Environment and Health, Munich, Germany.
Busch
Dirk H
DH
Eppinger
Elfriede
E
Kremmer
Elisabeth
E
Milosevic
Slavoljub
S
Hennard
Christine
C
Kuttler
Christina
C
Ellwart
Joachim W
JW
Frankenberger
Bernhard
B
Nössner
Elfriede
E
Salat
Christoph
C
Bogner
Christian
C
Borkhardt
Arndt
A
Kolb
Hans-Jochem
HJ
Krackhardt
Angela M
AM
D000951:Antigens, Neoplasm / Q000276:immunology; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D002999:Clone Cells; D003598:Cytoskeletal Proteins / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D000080865:Formins; D015234:HLA-A Antigens; D019337:Hematologic Neoplasms / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013950:Thymus Gland / Q000378:metabolism
D000951:Antigens, Neoplasm; D003598:Cytoskeletal Proteins; D018984:Epitopes, T-Lymphocyte; C476204:FMNL1 protein, human; D000080865:Formins; D015234:HLA-A Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell