CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.
CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.
复制标题
DOI：
10.1371/journal.pone.0061338
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sadelain M
中科院分区：
文献类型：
--
作者：
Davila ML;Kloss CC;Gunset G;Sadelain M
虽然许多患有B细胞急性淋巴细胞白血病（B-ALL）的成年人被诱导缓解，但大多数人会复发，强调了对这种疾病的新疗法的迫切需要。我们开发了鼠CD 19特异性嵌合抗原受体（汽车）和免疫活性小鼠模型的B-ALL，概括了疾病的遗传，细胞和病理水平。用与我们的临床试验中使用的CAR等同的全鼠CD 3 +/CD 28-基CAR转导的小鼠T细胞在小鼠中根除B-ALL并介导长期B细胞再生障碍。在该模型中，我们发现增加预处理化疗增加了肿瘤根除、B细胞再生障碍和CAR修饰的T细胞持久性。受体B谱系细胞的定量使我们能够估计用于B细胞再生障碍性贫血维持的体内效应物与内源性靶标的比率。在表现出显著B细胞减少的小鼠中，我们鉴定了骨髓中的一小群祖B细胞，其可以作为长期CAR修饰的T细胞刺激的储库。最后，我们确定单独输注CD 8 + CAR修饰的T细胞足以维持长期B细胞根除。我们在这里报告的小鼠模型应该被证明对研究基于CAR和其他成人B-ALL疗法有价值。
Although many adults with B cell acute lymphoblastic leukemia (B-ALL) are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs) and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.
登录
查看更多内容
影响因子：
82.9
作者：
Dierks, Christine;Grbic, Jovana;Warmuth, Markus
通讯作者：
Warmuth, Markus
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：
20.3
作者：
James, Scott E.;Orgun, Nural N.;Press, Oliver W.
通讯作者：
Press, Oliver W.
影响因子：
15.3
作者：
Li, Y S;Hayakawa, K;Hardy, R R
通讯作者：
Hardy, R R
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