Targeting FLT3-specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with KMT2A rearrangement
Targeting FLT3-specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with KMT2A rearrangement
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DOI：
10.1007/s00262-022-03303-4
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发表时间：
2022-10
期刊：
影响因子：
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通讯作者：
M. Suematsu;S. Yagyu;Hideki Yoshida;S. Osone;Y. Nakazawa;K. Sugita;T. Imamura;T. Iehara
中科院分区：
文献类型：
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作者：
M. Suematsu;S. Yagyu;Hideki Yoshida;S. Osone;Y. Nakazawa;K. Sugita;T. Imamura;T. Iehara
CD19特异性嵌合抗原受体T(CAR T)免疫疗法用于治疗B细胞恶性肿瘤。然而，抗原逃逸介导的复发在CAR-T治疗后已经成为一个主要的问题。在一些复发的病例中，特别是KMT2A重排阳性的B-急性淋巴细胞白血病(KMT2a-r B-ALL)，大多数B细胞抗原在向髓系表型转化的过程中丢失，导致多B细胞抗原靶向CAR T细胞治疗无效。FMS相关酪氨酸激酶-3(Flt3)在KMT2A-rB-ALL中高表达，因此，本研究旨在评价针对CD19和Flt3的CAR T细胞在KMT2A-rB-ALL细胞中的抗肿瘤作用。我们建立了针对CD19和/或Flt3的猪转座子介导的CAR T细胞(双重)，并通过CRISPR诱导的CD19基因敲除(KO)产生了CD19阴性的KMT2A-r B-ALL模型。Flt3 CAR T细胞在体内外对CD19-KOKMT2A-r B-ALL细胞均有杀伤作用，双靶向CAR T细胞对野生型(WT)和CD19-KOKMT2A-r B-ALL细胞有杀伤作用，而CD19 CAR T细胞在体外仅对WTKMT2A-r B-ALL细胞有杀伤作用。因此，即使在CD19阴性的复发病例中，靶向Flt3特异性CAR T细胞也将是KMT2A-r B-ALL细胞的一个有前途的策略。
CD19-specific chimeric antigen receptor T (CAR T) immunotherapy is used to treat B-cell malignancies. However, antigen-escape mediated relapse following CAR T therapy has emerged as a major concern. In some relapsed cases, especiallyKMT2Arearrangement-positive B-acute lymphoblastic leukemia (KMT2A-r B-ALL), most of the B-cell antigens are lost via lineage conversion to the myeloid phenotype, rendering multi-B-cell-antigen-targeted CAR T cell therapy ineffective. Fms-related tyrosine kinase-3 (FLT3) is highly expressed inKMT2A-r B-ALL; therefore, in this study, we aimed to evaluate the antitumor efficacy of CAR T cells targeting both CD19 and FLT3 inKMT2A-r B-ALL cells. We developedpiggyBactransposon-mediated CAR T cells targeting CD19, FLT3, or both (dual) and generated CD19-negativeKMT2A-r B-ALL models through CRISPR-induced CD19 gene-knockout (KO). FLT3 CAR T cells showed antitumor efficacy againstCD19-KOKMT2A-r B-ALL cells both in vitro and in vivo; dual-targeted CAR T cells showed cytotoxicity against wild-type (WT) andCD19-KOKMT2A-r B-ALL cells, whereas CD19 CAR T cells demonstrated cytotoxicity only against WTKMT2A-r B-ALL cells in vitro. Therefore, targeting FLT3-specific CAR T cells would be a promising strategy forKMT2A-r B-ALL cells even with CD19-negative relapsed cases.