Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.
Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.
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DOI：
10.1038/s41591-019-0737-3
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发表时间：
2020-02
期刊：
影响因子：
82.9
通讯作者：
Kochenderfer JN
中科院分区：
文献类型：
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作者：
Brudno JN;Lam N;Vanasse D;Shen YW;Rose JJ;Rossi J;Xue A;Bot A;Scholler N;Mikkilineni L;Roschewski M;Dean R;Cachau R;Youkharibache P;Patel R;Hansen B;Stroncek DF;Rosenberg SA;Gress RE;Kochenderfer JN
表达抗cd19嵌合抗原受体（CAR）的T细胞是治疗b细胞淋巴瘤的有效方法，但经常引起神经毒性。我们在I期临床试验中治疗了20例b细胞淋巴瘤患者，首次在人体中使用表达新型抗cd19 CAR Hu19-CD828Z （NCT02659943）的T细胞进行临床试验。主要目的是评估Hu19-CD828Z t细胞治疗的安全性和可行性。次要目的包括评估CAR - t细胞血液水平、抗淋巴瘤活性、二次输注和免疫原性。所有目标都达到了。55%接受Hu19-CD828Z T细胞治疗的患者获得完全缓解。Hu19-CD828Z T细胞具有与表达FMC63-28Z的T细胞相似的临床抗淋巴瘤活性，FMC63-28Z是我们小组先前测试的一种抗cd19 CAR，含有小鼠结合结构域，用于axicabtagene ciloleucel。然而，接受Hu19-CD828Z T细胞治疗的患者中只有5%发生了严重的神经毒性，而接受FMC63-28Z T细胞治疗的患者中有50%发生了严重的神经毒性（P=0.0017）。表达Hu19-CD828Z的T细胞释放的细胞因子水平低于表达FMC63-28Z的T细胞。与FMC63-28Z T细胞相比，接受Hu19-CD828Z T细胞治疗的患者血液中检测到较低水平的细胞因子，这可以解释Hu19-CD828Z治疗的神经毒性水平较低。表达CAR的T细胞释放的细胞因子水平特别依赖于CAR设计中包含的铰链和跨膜结构域。
Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are effective treatment for B-cell lymphoma but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-humans clinical trial of T cells expressing the novel anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of CAR T-cell blood levels, anti-lymphoma activity, second infusions, and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remissions. Hu19-CD828Z T cells had similar clinical anti-lymphoma activity as T cells expressing FMC63–28Z, an anti-CD19 CAR tested previously by our group that contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells versus 50% of patients who received FMC63–28Z T cells (P=0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63–28Z. Lower levels of cytokines were detected in blood of patients receiving Hu19-CD828Z T cells versus FMC63–28Z T cells, which could explain the lower level of neurologic toxicity with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.
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影响因子：
28.2
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
通讯作者：
Turtle CJ
DOI：
10.1097/cji.0b013e3181ac6138
发表时间：
2009-09
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Kochenderfer JN;Feldman SA;Zhao Y;Xu H;Black MA;Morgan RA;Wilson WH;Rosenberg SA
通讯作者：
Rosenberg SA
通过淋巴结消除来清除稳态细胞因子下沉，增强了采用转移的肿瘤特异性CD8+ T细胞的功效。
影响因子：
15.3
作者：
Gattinoni, Luca;Finkelstein, Steven E;Klebanoff, Christopher A;Antony, Paul A;Palmer, Douglas C;Spiess, Paul J;Hwang, Leroy N;Yu, Zhiya;Wrzesinski, Claudia;Heimann, David M;Surh, Charles D;Rosenberg, Steven A;Restifo, Nicholas P
通讯作者：
Restifo, Nicholas P
影响因子：
--
作者：
Bello, Martiniano;Correa-Basurto, Jose
通讯作者：
Correa-Basurto, Jose
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.