Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies

Abstract

The online version of this article has a Supplementary Appendix. BackgroundWe 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 MethodsEight 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. ResultsBoth 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 highavidity PR1 or WT1-specific CD8 + T cells could be detected, whereas low-avidity T cells were readily expanded. ConclusionsThese 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.

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia

“…The vaccine was generally well tolerated and the toxicity profile consistent with other WT1 vaccine-adjuvant combinations [21][22][23][24][25] ( Table 2). The montanide adjuvant is a known irritant, 26 and many of the most frequent toxicities consisted of mild to moderate local reactions and inflammation: injection site reaction (46%), fatigue (32%), skin induration (32%), and injection site pruritus (27%).…”

Mapping of novel peptides of WT-1 and presenting HLA alleles that induce epitope-specific HLA-restricted T cells with cytotoxic activity against WT-1+ leukemias

“…This may in part reflect the low levels and limited tissue distribution of WT-1 expression in healthy subjects. [18][19][20] Recently, Rezvani et al also demonstrated declining T-cell responses to WT-1 in patients repeatedly vaccinated with WT-1 peptides, 64 suggesting that these responses are highly regulated. Lehe et al have also recently shown that sensitization of T cells with a WT-1 peptide presented by DRB 1 0402 in the presence of high concentrations of IL-2 preferentially stimulates the generation of CD25 ϩ FOX P3 ϩ GITR ϩ CD127 Ϫ regulatory T cells capable of inhibiting CD8 ϩ WT-1-specific T-cell responses.…”

Novel Immunotherapy to Eliminate Minimal Residual Disease in AML Patients

“…A phase II clinical trial in AML and high-risk MDS using a WT1 peptide vaccine demonstrated that an immunologic response was observed in 44% patients, and objective clinical responses were observed in 10 out of 17 AML patients [18]. While there are reports from small case series which have suggested that WT1 vaccination can have long term efficacy in patients [19,20], other groups have observed that that repeated peptide vaccination in Montanide failed to induce sustained high-avidity, epitope-specific T cell responses in treated patients [21]. In addition, Lehe et al [22] generated WT1 specific T-cell clones which carried a CD4…”