Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.
Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.
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DOI：
10.1126/scitranslmed.3003761
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发表时间：
2012-05-02
影响因子：
17.1
通讯作者：
June CH
中科院分区：
文献类型：
--
作者：
Scholler J;Brady TL;Binder-Scholl G;Hwang WT;Plesa G;Hege KM;Vogel AN;Kalos M;Riley JL;Deeks SG;Mitsuyasu RT;Bernstein WB;Aronson NE;Levine BL;Bushman FD;June CH
过继性T细胞基因转移治疗癌症和HIV的成功取决于产生持久和安全的反应。在这里，我们报告了三项临床试验的长期结果，以评估γ逆转录病毒载体工程化的T细胞治疗HIV。该载体编码嵌合抗原受体（CAR），其由连接至CD 3-γ信号传导链（CD 4 γ）的CD 4组成。在输注后至少11年的98%的样本中检测到CAR T细胞，其频率超过大多数疫苗方法后的平均T细胞水平。CD 4 β转基因保留了表达和功能。没有证据表明载体诱导的细胞永生化，因为整合位点分布没有证据表明涉及生长控制或转化的基因附近的整合位点存在持续的克隆扩增或富集。CD 4 + T细胞具有稳定的植入水平，衰变半衰期超过16年，与之前测试工程化T细胞的试验形成鲜明对比。这些发现表明，为了实现基因修饰的T细胞的长期持久性，不需要在T细胞转移之前进行宿主免疫抑制。此外，我们的结果强调了逆转录病毒基因转移修饰的T细胞在临床应用中的安全性，如在>500患者年的随访中所测量的。因此，先前整合病毒载体的安全性问题是造血干细胞或转基因固有的，而不是逆转录病毒载体的一般特征。工程化T细胞是合成生物学的一种有前途的形式，用于长期递送基于蛋白质的治疗剂。这些结果提供了一个框架，以指导广泛的人类疾病的治疗。
The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. Here we report long term results from three clinical trials to evaluate gammaretroviral vector engineered T-cells for HIV. The vector encoded a chimeric antigen receptor (CAR) comprised of CD4 linked to the CD3-ζ signaling chain (CD4ζ). CAR T-cells were detected in 98% of samples tested for at least 11 years post-infusion at frequencies that exceed average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells as integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells have stable levels of engraftment, with decay half-lives that exceed 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression prior to T cell transfer is not required in order to achieve long term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient years of follow up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long term delivery of protein based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.
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影响因子：
4.8
作者：
Ciuffi, Angela;Ronen, Keshet;Brady, Troy;Malani, Nirav;Wang, Gary;Berry, Charles C.;Bushman, Frederic D.
通讯作者：
Bushman, Frederic D.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.4
作者：
Crotty, S;Felgner, P;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
20.3
作者：
Newrzela, Sebastian;Cornils, Kerstin;von Laer, Dorothee
通讯作者：
von Laer, Dorothee
影响因子：
6.7
作者：
Ocwieja KE;Brady TL;Ronen K;Huegel A;Roth SL;Schaller T;James LC;Towers GJ;Young JA;Chanda SK;König R;Malani N;Berry CC;Bushman FD
通讯作者：
Bushman FD