CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.
CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.
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DOI：
10.1038/srep11483
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发表时间：
2015-07-09
影响因子：
4.6
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Han J;Chu J;Keung Chan W;Zhang J;Wang Y;Cohen JB;Victor A;Meisen WH;Kim SH;Grandi P;Wang QE;He X;Nakano I;Chiocca EA;Glorioso Iii JC;Kaur B;Caligiuri MA;Yu J
胶质母细胞瘤（GB）仍然是最具侵袭性的原发性脑恶性肿瘤。嵌合抗原受体（CAR）修饰的免疫细胞的连续转移已经成为一种有前途的抗癌方法，但CAR工程化的自然杀伤（NK）细胞治疗GB的潜在效用尚未被探索。大约50%的GB患者的肿瘤表达野生型EGFR（wtEGFR），少数病例同时表达wtEGFR和突变型EGFRvIII;然而，先前报道的CAR T细胞研究仅关注靶向EGFRvIII。在这里，我们探索wtEGFR和EGFRvIII是否可以被CAR重定向的NK细胞有效靶向治疗GB。我们用携带靶向wtEGFR和EGFRvIII的第二代CAR的慢病毒构建体转导人NK细胞系NK-92和NKL以及原代NK细胞，并评估EGFR-CAR修饰的NK细胞的抗GB功效。当以EGFR依赖性方式与GB细胞或患者来源的GB干细胞共培养时，EGFR-CAR工程化NK细胞显示出增强的细胞溶解能力和IFN-γ产生。在两种原位GB异种移植小鼠模型中，NK-92-EGFR-CAR细胞的颅内给药导致肿瘤生长的有效抑制，并显著延长了荷瘤小鼠的生存期。这些发现支持颅内施用NK-92-EGFR-CAR细胞代表治疗GB的有希望的临床策略。
Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL, and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.
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影响因子：
3.7
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
通讯作者：
Holland E
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：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
影响因子：
5.7
作者：
Ohno, Masasuke;Natsume, Atsushi;Wakabayashi, Toshihiko
通讯作者：
Wakabayashi, Toshihiko
DOI：
10.1158/1078-0432.ccr-09-1322
发表时间：
2010-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ahmed N;Salsman VS;Kew Y;Shaffer D;Powell S;Zhang YJ;Grossman RG;Heslop HE;Gottschalk S
通讯作者：
Gottschalk S