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.

Design and 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. (ClinicalTrials.gov Identifier: NCT00499772)