Immune monitoring via WT1 epitope-specific IgM and IgG antibodies in patients treated with WT1 peptide vaccine cancer immunotherapy

概要

The Wilms’ tumor gene WT1 is highly expressed in various malignancies and plays oncogenic roles in these cancers. We have developed peptide-based cancer vaccine immunotherapy targeting WT1 (WT1 peptide vaccine). Monitoring host immunological status before vaccination and the induction of target-specific cellular immune responses are essential in cancer therapeutic vaccines. In the studies, I focused on IgM and IgG antibodies against WT1-235 epitope, which is the target of WT1 peptide vaccine. In humoral immune responses, IgM production is the first response and IgG class switching requires helper T cell help. These features in the production of antibodies indicate that WT1-specific IgM and IgG antibodies could be different types of immune monitoring markers in patients treated with WT1 peptide cancer vaccine. Further, we searched a novel antigenic WT1 epitope and identified WT1-271 epitope.

In the first paper, WT1 epitope-specific immune responses were analyzed in patients with advanced sarcoma with human leukocyte antigen-A*24:02- and WT1- expressing tumors who received the WT1-235 peptide vaccine as monotherapy. We found that 1) IgM antibodies against WT1-235 and WT1-271 were detected in three (9.6%) and 20 patients (64.5%), respectively, prior to vaccine administration, indicating immune recognition of the WT1 antigen prior to administering the vaccine. 2) An enzyme-linked immunospot assay revealed that WT1-235 epitope- specific IL-10 production/secretion in peripheral blood mononuclear cells declined in the first month of vaccine administration in all three patients with positivity for WT1-235 IgM at the start of the vaccine. 3) Positivity for both WT1-235 and WT1- 271 IgM antibodies at the start of treatment was associated with unfavorable tumor control at 3 months after vaccine administration. These results suggested that WT1 epitope-specific IgM antibodies may be utilized as immune-monitoring markers for evaluation of host immunological status before vaccination and could be prognostic markers. 4) WT1-235 IgG antibody levels were elevated in 33.3% of sarcoma patients during the three-month treatment protocol compared to GMB and ovarian cancer where approximately half of the patients were treated with the WT1-235 peptide cancer vaccine had elevated WT1-235 IgG antibody. These results suggest insufficient induction of WT1-235 specific immune responses in the majority of patients. [1].

In the second paper, we found a clear association between the production of WT1- 235 IgG antibody during the vaccination period and longer progression-free survival in patients with advanced or recurrent ovarian cancer treated with the WT1 peptide vaccine. These results are compatible with our previous findings that WT1-235 IgG antibody was associated with favorable clinical outcomes in recurrent glioblastoma patients treated with the WT1 peptide vaccine. These results indicate that WT1-235 IgG antibody may be a predictive biomarker for patients treated with the WT1 peptide vaccine immunotherapy. [2]

Conclusion: WT1 epitope-specific IgM and IgG antibodies may be useful biomarkers to evaluate host immunological status and the induction of WT1-specific immune responses in WT1 peptide-based cancer vaccine immunotherapy.