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WT1 PEPTIDE VACCINATION IN COMBINATION WITH IMATINIB THERAPY FOR A PATIENT WITH CML IN THE CHRONIC PHASE
We aimed to clarify the safety and effects of WT1 peptide vaccination in combination with imatinib therapy for a CML patient. A 51 year-old male with CML in CP, who showed a resistance against imatinib therapy for 2.5 years, began to be treated with 9mer modified-type WT1 peptides in combination with standard dose of imatinib. Although every 2-week-administration of WT1 peptides for 22 weeks did not show definite effects on the quantification of bcr-abl transcripts, by changing the administration from every 2 weeks to 4 weeks bcr-abl transcripts decreased remarkably. After 11 months of every 4-week-administration of the peptides and 12 months post cessation of the peptides bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response). WT1/MHC tetramer+CD8+ CTLs, which appeared after the second administration of WT1 peptides and remained more than 15 in number among 106 CD8+ T cells throughout the administration of WT1 peptides, are still present in the blood on 14th month post cessation of the peptides. An in vitro study as to the cytotoxicity of lymphocytes induced by mixed lymphocyte peptide culture demonstrated that cultured lymphocytes possessed cytotoxicity against WT1 expressing leukemia cells and the cytotoxicity was WT1-specific and MHC class I restricted. The present study showed that WT1 peptide vaccination in combination with TKI is feasible and effective in the therapy for imatinib-resistant CML.
Clinical efficacy of WT1 peptide vaccination
A 51 year-old male with CML in chronic phase had been treated with 400 mg imatinib for two and a half years. Although bcr-abl transcripts decreased transiently to less than 1,000 copies in 1 μg RNA extracted from PB cells (3-log reduction = 280 copies in 1 μg cellular RNA; median in our laboratory, n=120) during the imatinib treatment, the transcripts gradually increased to more than 4,000 copies spontaneously thereafter. Imatinib was increased to a dose of 600 mg and continued for 4 months, which caused adverse effects such as worsening of anemia and limb pain with increased CK. Therefore the dose of imatinib was decreased to 400 mg. Thereafter bcr-abl transcripts decreased transiently to 500 copies during the imatinib treatment, which was speculated to be the late effects of imatinib therapy at the dose of 600 mg a day. However, bcr-abl transcripts gradually increased to more than 1,000 copies thereafter. Since the patient was HLA-A*2402+ and informed consent was obtained, modified-type WT1 peptides, which had been identified to possess an anti-tumor immunogenicity [7], were administered subcutaneously at the dose of 1 mg every 2 weeks in combination with 400 mg imatinib. After the second administration of the peptides, WT1 peptide/HLA-A*2402 (WT1/MHC) tetramer+CD8+ T cells began to be detected in PB at a frequency of 7x10-6 in PB-CD8+ T cells. After the fourth administration of WT1 peptides, bcr-abl transcripts decreased to 820 copies with an increase in the frequency of WT1/MHC tetramer+CD8+ T cells in PB. However, bcr-abl transcripts increased to more than 1,000 copies after the eighth administration of WT1 peptides, though the frequencies of WT1/MHC tetramer+CD8+ T cells in PB were maintained at a considerable level. Since there was a report that some anti-tumor CD8+ CTLs lose their cytolytic activity by strong antigenic stimulation [9], the interval of WT1 peptide administration was changed from two weeks to four weeks after the eleventh administration of WT1 peptides. Although bcr-abl transcripts rose up to 2,600 copies after 12th administration of WT1 peptides, thereafter the transcripts tended to decrease and fell to 400 copies after 22nd administration of WT1 peptides. After seven months from the cessation of WT1 peptide vaccination bcr-abl transcripts decreased to the level of a major molecular response (170 copies). Four months thereafter, bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response) (Fig. 1). WT1/MHC tetramer+CD8+ CTLs are still present in the blood on 14th month post cessation of the peptides. No adverse effects due to WT1 peptide vaccination was observed except for skin induration and redness at the sites of WT1 peptide injection.