Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia.
Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia.
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DOI：
10.1182/bloodadvances.2022008304
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发表时间：
2023-04-11
期刊：
影响因子：
7.5
通讯作者：
Meshinchi, Soheil
中科院分区：
文献类型：
--
作者：
Kirkey, Danielle C.;Loeb, Anisha M.;Castro, Sommer;McKay, Cyd Nourigat;Perkins, LaKeisha;Pardo, Laura;Leonti, Amanda R.;Tang, Thao T.;Loken, Michael R.;Brodersen, Lisa Eidenschink;Loeb, Keith R.;Scheinberg, David A.;Le, Quy;Meshinchi, Soheil
PRAME在儿童和成人急性髓性白血病中异常表达，在正常造血细胞中不存在。模拟TCR CAR T细胞在体外和体内异种移植模型中有效靶向PRAME。黑色素瘤前表达抗原（PRAME）是一种肿瘤-睾丸抗原，为急性髓系白血病（AML）的免疫治疗提供了理想的靶点。我们已经显示PRAME在儿童和成人AML的重要子集中表达，并且在正常造血中缺乏表达。虽然是细胞内抗原，但我们开发了一种使用嵌合抗原受体（CAR）构建体靶向PRAME的新方法，所述嵌合抗原受体构建体编码基于靶向肽-HLA复合物的T细胞受体（TCR）模拟抗体的靶向结构域。我们使用了来自先前设计的TCR模拟物（mTCR）抗体Pr 20的抗体序列，其识别与HLA-A β 02复合的PRAME ALY肽，并验证了PRAME在AML细胞系和原代AML母细胞中的表达。使用Pr 20抗体序列，我们开发了CAR T细胞（PRAME mTCRCAR T），以针对来自AML患者的原代样品和在HLA-A2表达的背景下表达PRAME抗原的AML细胞系进行测试。与适当的对照相比，PRAME mTCRCAR T细胞在OCI-AML 2和THP-1细胞系、表达PRAME抗原的HLA-A2细胞系中以及针对原代AML患者样品显示出靶特异性和HLA介导的体外活性。与未修饰的T细胞对照相比，用PRAME mTCRCAR T细胞处理的体内细胞衍生的异种移植物模型显示出有效的白血病清除和改善的存活。此外，PRAME mTCRCAR T细胞的细胞溶解活性通过用干扰素γ处理靶细胞而增强，干扰素γ增加PRAME抗原表达。这些结果证明了用新型PRAME mTCRCAR T细胞靶向PRAME的可行性和功效。
PRAME is aberrantly expressed in childhood and adult acute myeloid leukemia and is absent in normal hematopoietic cells. Mimic TCR CAR T cells effectively target PRAME in vitro and in vivo xenograft models. Preferentially Expressed Antigen in Melanoma (PRAME), a cancer-testis antigen, provides an ideal target for immunotherapy in acute myeloid leukemia (AML). We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a chimeric antigen receptor (CAR) construct encoding a targeting domain based on T-cell receptor (TCR) mimic antibodies that target the peptide-HLA complex. We used the antibody sequence from a previously designed TCR mimic (mTCR) antibody, Pr20, that recognizes the PRAME ALY peptide in complex with HLA-A∗02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary samples from patients with AML and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to appropriate controls, PRAME mTCRCAR T cells demonstrate target-specific and HLA-mediated in vitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. In vivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared with unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with interferon gamma, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.
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影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA
DOI：
10.1158/1078-0432.ccr-21-1546
发表时间：
2021-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
通讯作者：
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影响因子：
3.8
作者：
Doolan, Padraig;Clynes, Martin;O'Driscoll, Lorraine
通讯作者：
O'Driscoll, Lorraine
影响因子：
6.4
作者：
Greiner, J;Ringhoffer, M;Schmitt, M
通讯作者：
Schmitt, M