Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies.
BACKGROUND
We previously showed that vaccination with one dose of PR1 and WT1 peptides induces transient anti-leukemia immunity. We hypothesized that maintenance of a sustained anti-leukemia response may require frequent boost injections.


METHODS
Eight patients with myeloid malignancies were enrolled in this phase II study, and 6 completed 6 injections of PR1 and WT1 peptides in Montanide-adjuvant with GM-CSF, every two weeks.


RESULTS
Both high- and low-avidity PR1 or WT1-specific CD8(+) T cells were detected in all evaluable patients after the first vaccine dose. Repeated vaccination led to selective deletion of high avidity PR1- and WT1-specific CD8(+) T cells and was not associated with significant reduction in WT1-expression. Additional boosting failed to increase vaccine-induced CD8(+) T-cell frequencies further and in all patients the response was lost before the 6(th) dose. PR1- or WT1-specific CD8(+) T cells were not detected in bone marrow samples, excluding their preferential localization to this site. Following a booster injection three months after the 6(th) vaccine dose, no high-avidity PR1 or WT1-specific CD8(+) T cells could be detected, whereas low-avidity T cells were readily expanded.


CONCLUSIONS
These data support the immunogenicity of PR1 and WT1 peptide vaccines. However, repeated delivery of peptides with Montanide-adjuvant and GM-CSF leads to rapid loss of high-avidity peptide-specific CD8(+) T cells. These results may offer an explanation for the lack of correlation between immune and clinical responses observed in a number of clinical trials of peptide vaccination. New approaches are needed to induce long-term high-avidity memory responses against leukemia antigens.
Department of Hematology, Imperial College, Hammersmith Campus, 4th Floor, Commonwealth Building, DuCane Rd, London W12 0NN, UK. k.rezvani@imperial.ac.uk
Katayoun
K
Rezvani
Agnes S M
AS
Yong
Stephan
S
Mielke
Behnam
B
Jafarpour
Bipin N
BN
Savani
Robert Q
RQ
Le
Rhoda
R
Eniafe
Laura
L
Musse
Carol
C
Boss
Roger
R
Kurlander
A John
AJ
Barrett
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D000939:Epitopes / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007114:Immunization; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D025721:WT1 Proteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D000939:Epitopes; D022223:Vaccines, Subunit; D025721:WT1 Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor