Inducible Caspase-9 Selectively Modulates the Toxicities of CD19-Specific Chimeric Antigen Receptor-Modified T Cells

被引：201

作者：

Diaconu, Iulia ^{[1
,2
]}

Ballard, Brandon ^{[1
,2
]}

Zhang, Ming ^{[1
,2
]}

Chen, Yuhui ^{[7
]}

West, John ^{[6
]}

Dotti, Gianpietro ^{[1
,2
,3
,4
,6
]}

Savoldols, Barbara ^{[1
,2
,5
,7
]}

机构：

[1] Methodist Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA

[2] Texas Childrens Hosp, Houston, TX 77030 USA

[3] Methodist Hosp, Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[4] Methodist Hosp, Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA

[5] Methodist Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[6] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pediat, Chapel Hill, NC 27599 USA

来源：

MOLECULAR THERAPY | 2017年 / 25卷 / 03期

关键词：

ENGINEERED DONOR LYMPHOCYTES; SUICIDE-GENE; IN-VIVO; SAFETY SWITCH; EXPANSION; CYTOKINE; INFUSION; LEUKEMIA; ENHANCE;

D O I：

10.1016/j.ymthe.2017.01.011

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Immunotherapy with T cells expressing the chimeric antigen receptor (CAR) specific for the CD19 antigen (CD19.CAR-Ts) is a very effective treatment in B cell lymphoid malignancies. However, B cell aplasia and cytokine release syndrome (CRS) secondary to the infusion of CD19.CAR-Ts remain significant drawbacks. The inclusion of safety switches into the vector encoding the CAR is seen as the safest method to terminate the effects of CD19.CAR-Ts in case of severe toxicities or after achieving long-term sustained remissions. By contrast, the complete elimination of CD19.CAR-Ts when CRS occurs may jeopardize clinical responses as CRS and antitumor activity seem to concur. We have demonstrated, in a humanized mouse model, that the inducible caspase-9 (iC9) safety switch can eliminate CD19.CAR-Ts in a dose-dependent manner, allowing either a selective containment of CD19.CAR-T expansion in case of CRS or complete deletion on demand granting normal B cell reconstitution.

引用

页码：580 / 592

页数：13

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