High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells
High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells
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DOI：
10.1182/blood-2010-08-300376
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发表时间：
2011-03-24
期刊：
影响因子：
20.3
通讯作者：
Savoldo, Barbara
中科院分区：
文献类型：
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作者：
Quintarelli, Concetta;Dotti, Gianpietro;Savoldo, Barbara
癌症睾丸抗原（CTA）优先表达的黑色素瘤抗原（PRAME）在许多血液恶性肿瘤中过表达，但在正常组织（包括造血祖细胞）中不存在，因此可能是T细胞介导的免疫治疗的合适候选者。因为有效的抗肿瘤反应可能需要高亲合力的PRAME特异性细胞毒性T淋巴细胞（CTL），我们尝试使用装载有肽文库的专业和人工抗原呈递细胞来产生这样的CTL，所述肽文库跨越整个PRAME蛋白并且由125个合成的十五肽重叠11个氨基酸组成。我们成功地产生了多克隆的PRAME特异性CTL系，并引发了高亲和力CTL，其中高比例的细胞识别以前未研究的HLA-A*02限制性表位P435- 9 mer（NLTHVLYPV）。这些PRAME-CTL可以从正常供体和患有PRAME（+）恶性血液病的受试者产生。我们的PRAME特异性CTL的细胞毒性活性不仅针对白血病母细胞，而且针对白血病祖细胞，如通过集落形成抑制测定所评估的，其与白血病复发有关。这些PRAME导向的CTL不影响正常造血祖细胞，表明这种方法可能对PRAME（+）恶性血液病的免疫治疗有价值。（血。2011; 117（12）：3353-3362）
The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed by many hematologic malignancies, but is absent on normal tissues, including hematopoietic progenitor cells, and may therefore be an appropriate candidate for T cell-mediated immunotherapy. Because it is likely that an effective antitumor response will require high-avidity, PRAME-specific cytotoxic T lymphocytes (CTLs), we attempted to generate such CTLs using professional and artificial antigen-presenting cells loaded with a peptide library spanning the entire PRAME protein and consisting of 125 synthetic pentadecapeptides overlapping by 11 amino acids. We successfully generated polyclonal, PRAME-specific CTL lines and elicited high-avidity CTLs, with a high proportion of cells recognizing a previously uninvestigated HLA-A*02-restricted epitope, P435-9mer (NLTHVLYPV). These PRAME-CTLs could be generated both from normal donors and from subjects with PRAME(+) hematologic malignancies. The cytotoxic activity of our PRAME-specific CTLs was directed not only against leukemic blasts, but also against leukemic progenitor cells as assessed by colony-forming-inhibition assays, which have been implicated in leukemia relapse. These PRAME-directed CTLs did not affect normal hematopoietic progenitors, indicating that this approach may be of value for immunotherapy of PRAME(+) hematologic malignancies. (Blood. 2011; 117(12):3353-3362)