Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia.
The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8(+) T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM(+) CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2(+) CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 microg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 microg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I degrees skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8(+) T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8(+) T cells that expressed high levels of CD107a and produced both interferon-gamma and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8(+) T-cell responses against the tumor antigen RHAMM.
Giannopoulos
K
K
Clinical Immunology Department, Medical University of Lublin, Lublin, Poland. giannop@tlen.pl
Dmoszynska
A
A
Kowal
M
M
Rolinski
J
J
Gostick
E
E
Price
D A
DA
Greiner
J
J
Rojewski
M
M
Stilgenbauer
S
S
Döhner
H
H
Schmitt
M
M
D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins / Q000276:immunology*; D005240:Feasibility Studies; D005260:Female; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000628:therapy; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014611:Vaccination
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins; D015789:HLA-A2 Antigen; D018960:Hyaluronan Receptors; D010446:Peptide Fragments; C098946:hyaluronan-mediated motility receptor; D007371:Interferon-gamma