Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor.
Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor.
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作者：
Chen KH;Wada M;Pinz KG;Liu H;Lin KW;Jares A;Firor AE;Shuai X;Salman H;Golightly M;Lan F;Senzel L;Leung EL;Jiang X;Ma Y
由于缺乏有效的治疗选择，T细胞恶性肿瘤的前景仍然很差。嵌合抗原受体（CAR）免疫疗法最近在B细胞恶性肿瘤的临床试验中显示出前景，然而，由于正常和恶性T细胞之间共享的表面抗原库，设计用于基于T细胞的疾病的汽车仍然是一个挑战。正常T细胞表达CD 5，但NK（自然杀伤）细胞不表达，将NK细胞定位为用于CD 5CAR设计的有吸引力的细胞毒性细胞。此外，CD 5在T细胞急性淋巴细胞白血病（T-ALL）和外周T细胞淋巴瘤（PTCL）中高度表达。在这里，我们报告了一种稳健的抗CD 5 CAR（CD 5CAR）转导到人NK细胞系NK-92中，可以进行稳定的体外扩增。我们发现，CD 5CAR NK-92细胞对多种T细胞白血病和淋巴瘤细胞系以及原发性肿瘤细胞具有一致的、特异性的和有效的抗肿瘤活性。此外，我们能够证明在T-ALL异种移植小鼠模型中显着抑制和控制疾病进展。这些数据表明，使用NK细胞的CAR重定向靶向T细胞恶性肿瘤可能是一种可行的新的补充治疗方法，可以改善患者的当前结果。
The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients.
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影响因子：
7.3
作者：
Klingemann H;Boissel L;Toneguzzo F
通讯作者：
Toneguzzo F
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：
11.4
作者：
通讯作者：
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影响因子：
5.3
作者：
Romanski A;Uherek C;Bug G;Seifried E;Klingemann H;Wels WS;Ottmann OG;Tonn T
通讯作者：
Tonn T
影响因子：
2.7
作者：
Boissel L;Betancur M;Wels WS;Tuncer H;Klingemann H
通讯作者：
Klingemann H