Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma.
Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma.
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DOI：
10.1016/j.omto.2021.03.001
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发表时间：
2021-03-26
期刊：
影响因子：
--
通讯作者：
Hosoi H
中科院分区：
文献类型：
--
作者：
Kubo H;Yagyu S;Nakamura K;Yamashima K;Tomida A;Kikuchi K;Iehara T;Nakazawa Y;Hosoi H
在包括横纹肌肉瘤在内的肿瘤中表达的肝配蛋白B型受体4（EPHB 4）是嵌合抗原受体（CAR）-T细胞的合适靶标。EPHB 4的配体非依赖性激活导致横纹肌肉瘤中的细胞增殖和恶性转化，而EPHB 4的配体依赖性刺激诱导横纹肌肉瘤中的细胞凋亡。因此，我们假设基于配体的EPHB 4特异性CAR-T细胞可以杀死横纹肌肉瘤细胞，而不会刺激下游细胞增殖机制。我们通过EPHRIN B2（EPHB 4的天然配体）靶向EPHB 4开发了新型CAR-T细胞。通过基于piggyBac（PB）转座子的基因转移产生EPHB 4-CAR-T细胞导致足够的T细胞扩增和CAR阳性（78.5% ± 5.9%）。在扩增14天后，PB-EPHB 4-CAR-T细胞显示出显性干细胞记忆分数（59.4% ± 7.2%）以及低PD-1表达（0.60% ± 0.21%）。PB-EPHB 4-CAR-T细胞抑制EPHB 4阳性肿瘤细胞，而不激活EPHB 4下游的细胞增殖，即使在多次肿瘤再激发后也是如此，并抑制了异种移植小鼠的肿瘤生长。因此，PB-EPHB 4-CAR-T细胞具有丰富的记忆部分，而没有早期T细胞耗竭，并显示出作为治疗横纹肌肉瘤和其他EPHB 4阳性肿瘤的有前景的治疗剂的潜力。靶向EPHB 4的piggyBac转座子介导的CAR-T细胞疗法表现出足够的CAR阳性、稳定的CAR表达、有利的表型和针对EPHB 4阳性肿瘤的强抗肿瘤功效，并且将有希望用于治疗恶性横纹肌肉瘤。
Ephrin type-B receptor 4 (EPHB4), expressed in tumors including rhabdomyosarcoma, is a suitable target for chimeric antigen receptor (CAR)-T cells. Ligand-independent activation of EPHB4 causes cell proliferation and malignant transformation in rhabdomyosarcoma, whereas ligand-dependent stimulation of EPHB4 induces apoptosis in rhabdomyosarcoma. Therefore, we hypothesized that ligand-based, EPHB4-specific CAR-T cells may kill rhabdomyosarcoma cells without stimulating downstream cell proliferation mechanisms. We developed novel CAR-T cells by targeting EPHB4 via EPHRIN B2, a natural ligand of EPHB4. The generation of EPHB4-CAR-T cells via piggyBac (PB) transposon-based gene transfer resulted in sufficient T cell expansion and CAR positivity (78.5% ± 5.9%). PB-EPHB4-CAR-T cells displayed a dominant stem cell memory fraction (59.4% ± 7.2%) as well as low PD-1 expression (0.60% ± 0.21%) after 14 days of expansion. The PB-EPHB4-CAR-T cells inhibited EPHB4-positive tumor cells without activating cell proliferation downstream of EPHB4, even after multiple tumor re-challenges and suppressed tumor growth in xenograft-bearing mice. Therefore, PB-EPHB4-CAR-T cells possess a memory-rich fraction without early T cell exhaustion and show potential as promising therapeutic agents for treating rhabdomyosarcoma and other EPHB4-positive tumors. piggyBac transposon-mediated CAR-T cell therapy targeting EPHB4 exhibited sufficient CAR positivity, stable CAR expression, a favorable phenotype, and strong antitumor efficacy against EPHB4-positive tumors and would be promising for the treatment of malignant rhabdomyosarcomas.
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影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
20.3
作者：
Louis, Chrystal U.;Savoldo, Barbara;Brenner, Malcolm K.
通讯作者：
Brenner, Malcolm K.
影响因子：
3.8
作者：
Djokovic D;Trindade A;Gigante J;Badenes M;Silva L;Liu R;Li X;Gong M;Krasnoperov V;Gill PS;Duarte A
通讯作者：
Duarte A
影响因子：
3.7
作者：
Ferguson BD;Liu R;Rolle CE;Tan YH;Krasnoperov V;Kanteti R;Tretiakova MS;Cervantes GM;Hasina R;Hseu RD;Iafrate AJ;Karrison T;Ferguson MK;Husain AN;Faoro L;Vokes EE;Gill PS;Salgia R
通讯作者：
Salgia R
DOI：
10.1158/1078-0432.ccr-15-0428
发表时间：
2015-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brown CE;Badie B;Barish ME;Weng L;Ostberg JR;Chang WC;Naranjo A;Starr R;Wagner J;Wright C;Zhai Y;Bading JR;Ressler JA;Portnow J;D'Apuzzo M;Forman SJ;Jensen MC
通讯作者：
Jensen MC