Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan.
Int J Med Sci. 2010 Apr 20;7(2):72-81. doi: 10.7150/ijms.7.72.
Although tyrosine kinase inhibitors is effective for dramatically reducing CML cells, it might be difficult to eradicate completely the CML stem cells. 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 9 mer 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 10(6) 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.
尽管酪氨酸激酶抑制剂对于显著减少 CML 细胞非常有效，但可能难以彻底消除 CML 干细胞。我们旨在阐明 WT1 肽疫苗接种联合伊马替尼治疗 CML 患者的安全性和效果。一名 51 岁男性，患有 CP 期 CML，对伊马替尼治疗产生 2.5 年耐药，开始接受 9 mer 改良型 WT1 肽与标准剂量伊马替尼联合治疗。尽管 22 周内每 2 周给予 WT1 肽 22 周并未对 bcr-abl 转录本的定量产生明确影响，但通过将给药方案从每 2 周改为每 4 周，bcr-abl 转录本显著下降。在每 4 周给予肽 11 个月后和停止肽治疗 12 个月后，bcr-abl 转录本达到 RQ/RT-PCR（完全分子反应）检测水平以下。WT1/MHC 四聚体（+）CD8（+）CTL 在第二次给予 WT1 肽后出现，并在整个 WT1 肽给药期间在 10（6）CD8（+）T 细胞中保持超过 15 个，在停止肽治疗后 14 个月仍存在于血液中。混合淋巴细胞肽培养诱导的淋巴细胞细胞毒性的体外研究表明，培养的淋巴细胞对表达 WT1 的白血病细胞具有细胞毒性，并且该细胞毒性是 WT1 特异性和 MHC Ⅰ类限制的。本研究表明，WT1 肽疫苗接种联合 TKI 治疗伊马替尼耐药性 CML 是可行且有效的。
