CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.
CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.
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DOI：
10.1038/s41591-021-01497-1
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发表时间：
2021-10
期刊：
影响因子：
82.9
通讯作者：
Amrolia PJ
中科院分区：
文献类型：
--
作者：
Cordoba S;Onuoha S;Thomas S;Pignataro DS;Hough R;Ghorashian S;Vora A;Bonney D;Veys P;Rao K;Lucchini G;Chiesa R;Chu J;Clark L;Fung MM;Smith K;Peticone C;Al-Hajj M;Baldan V;Ferrari M;Srivastava S;Jha R;Arce Vargas F;Duffy K;Day W;Virgo P;Wheeler L;Hancock J;Farzaneh F;Domning S;Zhang Y;Khokhar NZ;Peddareddigari VGR;Wynn R;Pule M;Amrolia PJ
靶向CD 19或CD 22的嵌合抗原受体（CAR）T细胞在B细胞急性淋巴细胞白血病（B-ALL）中显示出显著的活性。治疗失败的主要原因是抗原下调或丢失。双重抗原靶向可能会预防这种情况，但靶向CD 19和CD 22的CAR T细胞的临床安全性和有效性仍不清楚。我们在患有复发性或难治性B-ALL的儿童和年轻成人患者（n = 15）中进行了一项I期试验，以检测AUTO 3，即表达抗CD 19和抗CD 22汽车的自体转导T细胞（AMELIA试验，EUDRA CT 2016-004680-39）。主要终点为剂量限制性毒性阶段3-5级毒性的发生率和剂量限制性毒性的频率。次要终点包括形态学缓解率（完全缓解或完全缓解伴骨髓不完全恢复）和最小残留疾病阴性反应，以及不良事件的频率和严重程度、AUTO 3的扩增和持续性、B细胞再生障碍的持续时间以及总生存期和无事件生存期。符合研究终点。AUTO 3显示出良好的安全性特征，没有报告剂量限制性毒性或AUTO 3相关的严重细胞因子释放综合征或神经毒性的病例。治疗后1个月，缓解率（即完全缓解或完全缓解伴骨髓不完全恢复）为86%（13/15例患者）。1年总生存率和无事件生存率分别为60%和32%。复发可能是由于有限的长期AUTO 3持久性。需要改善CAR T细胞持久性的策略，以充分实现B-ALL中双重靶向CAR T细胞疗法的潜力。靶向CD 19和CD 22的双顺反子CAR T细胞在患有B细胞急性淋巴细胞白血病的儿童和年轻成人患者中表现出临床活性和低毒性，复发与有限的CAR T细胞持久性相关。
Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL. Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.
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DOI：
10.4049/jimmunol.1302101
发表时间：
2013-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Paul S;Weiskopf D;Angelo MA;Sidney J;Peters B;Sette A
通讯作者：
Sette A
抗体结构，结合同源性建模，基于能量的改进和环路预测的组合。
影响因子：
2.9
作者：
Zhu K;Day T;Warshaviak D;Murrett C;Friesner R;Pearlman D
通讯作者：
Pearlman D
影响因子：
28.5
作者：
Porter D;Frey N;Wood PA;Weng Y;Grupp SA
通讯作者：
Grupp SA
DOI：
10.1038/nrc3322
发表时间：
2012-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Gattinoni L;Klebanoff CA;Restifo NP
通讯作者：
Restifo NP
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