CD19-CAR-T Cells Bearing a KIR/PD-1-Based Inhibitory CAR Eradicate CD19(+)HLA-C1(-) Malignant B Cells While Sparing CD19(+)HLA-C1(+) Healthy B Cells.
CD19-CAR-T Cells Bearing a KIR/PD-1-Based Inhibitory CAR Eradicate CD19(+)HLA-C1(-) Malignant B Cells While Sparing CD19(+)HLA-C1(+) Healthy B Cells.
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携带基于 KIR/PD-1 的抑制性 CAR 的 CD19-CAR-T 细胞可根除 CD19( )HLA-C1(-) 恶性 B 细胞，同时保留 CD19( )HLA-C1( ) 健康 B 细胞
DOI：
10.3390/cancers12092612
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发表时间：
2020-09-13
期刊：
影响因子：
5.2
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Tao L;Farooq MA;Gao Y;Zhang L;Niu C;Ajmal I;Zhou Y;He C;Zhao G;Yao J;Liu M;Jiang W
靶向CD 19的嵌合抗原受体（CAR）T（CD 19-CAR-T）细胞疗法通常会因“中靶脱瘤”毒性而导致B细胞再生障碍。该研究的目的是评估将抑制性CAR（iCAR）引入CAR-T细胞可以减轻CD 19-CAR-T细胞治疗的副作用的概念。结果显示，具有基于新型KIR（杀伤抑制受体）/PD-1（程序性死亡受体-1）的抑制性CAR（iKP-19-CAR-T）的CD 19-CAR-T细胞表现出更幼稚、更少耗竭的表型，并保留了更高比例的中枢记忆T细胞（TCM）。此外，与CD 19-CAR-T细胞相比，iKP-19-CAR-T细胞对CD 19 +HLA-C1− Burkitt淋巴瘤细胞的细胞毒性水平相似，而在体外和异种移植模型中均不影响CD 19 +HLA-C1+健康人B细胞。我们的数据表明，基于KIR/PD-1的抑制性CAR可以是避免由CD 19-CAR-T细胞疗法引起的B细胞再生障碍性贫血的有希望的策略。由“中靶脱瘤”毒性引起的B细胞再生障碍性贫血是CD 19靶向嵌合抗原受体（CAR）T（CD 19-CAR-T）细胞治疗B细胞恶性肿瘤期间的临床副作用之一。在所有持续缓解的患者中观察到持续性B细胞再生障碍性贫血，这增加了患者感染的风险。有些病人甚至因感染而死亡。为了克服这一挑战，引入了将抑制性CAR（iCAR）并入CAR-T细胞的概念，以在发生“靶向脱瘤”事件时限制T细胞应答。在这项研究中，我们通过融合杀伤细胞免疫球蛋白样受体（KIR）2DL 2（KIR 2DL 2）的胞外结构域和PD-1的胞内结构域，设计了一种新的基于KIR/PD-1的抑制性CAR（iKP CAR）。我们还证实了iKP CAR可以通过PD-1结构域和携带iKP CAR的CD 19-CAR-T细胞抑制CD 19 CAR活化信号（iKP-19-CAR-T）在与CD 19-CAR-T细胞平行的CD 19 +HLA-C1− Burkitt淋巴瘤异种移植模型中表现出稳健的体外细胞毒性和抗肿瘤活性，同时在体外和异种移植模型中保留CD 19 +HLA-C1+健康人B细胞。同时，iKP-19-CAR-T细胞表现出更幼稚、更少耗竭的表型，并保留了更高比例的中央记忆T细胞（TCM）。我们的数据表明，基于KIR/PD-1的抑制性CAR可以是预防由CD 19-CAR-T细胞疗法诱导的B细胞再生障碍性贫血的有前景的策略。
CD19-targeted chimeric antigen receptor (CAR) T (CD19-CAR-T) cell therapy usually causes B cell aplasia because of “on-target off-tumor” toxicity. The aim of the study was to assess the concept that the introduction of an inhibitory CAR (iCAR) into CAR-T cells could alleviate the side effect of CD19-CAR-T cell therapy. The results showed that CD19-CAR-T cells with a novel KIR (killer inhibitory receptor) /PD-1 (programmed death receptor-1)-based inhibitory CAR (iKP-19-CAR-T) exhibited more naïve, less exhausted phenotypes and preserved a higher proportion of central memory T cells (TCM). Furthermore, iKP-19-CAR-T cells exerted the similar level of cytotoxicity on CD19+HLA-C1− Burkitt’s lymphoma cells compared to CD19-CAR-T cells while sparing CD19+HLA-C1+ healthy human B cells both in vitro and in the xenograft model. Our data demonstrates that the KIR/PD-1-based inhibitory CAR can be a promising strategy to avoid B cell aplasia caused by CD19-CAR-T cell therapy. B cell aplasia caused by “on-target off-tumor” toxicity is one of the clinical side effects during CD19-targeted chimeric antigen receptor (CAR) T (CD19-CAR-T) cells treatment for B cell malignancies. Persistent B cell aplasia was observed in all patients with sustained remission, which increased the patients’ risk of infection. Some patients even died due to infection. To overcome this challenge, the concept of incorporating an inhibitory CAR (iCAR) into CAR-T cells was introduced to constrain the T cells response once an “on-target off-tumor” event occurred. In this study, we engineered a novel KIR/PD-1-based inhibitory CAR (iKP CAR) by fusing the extracellular domain of killer cell immunoglobulin-like receptors (KIR) 2DL2 (KIR2DL2) and the intracellular domain of PD-1. We also confirmed that iKP CAR could inhibit the CD19 CAR activation signal via the PD-1 domain and CD19-CAR-T cells bearing an iKP CAR (iKP-19-CAR-T) exerted robust cytotoxicity in vitro and antitumor activity in the xenograft model of CD19+HLA-C1− Burkitt’s lymphoma parallel to CD19-CAR-T cells, whilst sparing CD19+HLA-C1+ healthy human B cells both in vitro and in the xenograft model. Meanwhile, iKP-19-CAR-T cells exhibited more naïve, less exhausted phenotypes and preserved a higher proportion of central memory T cells (TCM). Our data demonstrates that the KIR/PD-1-based inhibitory CAR can be a promising strategy for preventing B cell aplasia induced by CD19-CAR-T cell therapy.
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影响因子：
17.1
作者：
Fedorov VD;Themeli M;Sadelain M
通讯作者：
Sadelain M
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
8.8
作者：
Mizukami Y;Kono K;Maruyama T;Watanabe M;Kawaguchi Y;Kamimura K;Fujii H
通讯作者：
Fujii H
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
带有嵌合抗原受体的T细胞具有有效的抗肿瘤作用，可以在晚期白血病患者中建立记忆。
影响因子：
17.1
作者：
Kalos M;Levine BL;Porter DL;Katz S;Grupp SA;Bagg A;June CH
通讯作者：
June CH