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Mol Ther. 2017 Mar 1;25(3):580-592. doi: 10.1016/j.ymthe.2017.01.011. Epub 2017 Feb 8.

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

Author information

1
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA.
2
Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
4
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA; Department of Immunology, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA; Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
5
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatric, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: bsavoldo@med.unc.edu.

Abstract

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.

KEYWORDS:

adoptive immunotherapy; chimeric antigen receptor; safety switch

PMID:
28187946
PMCID:
PMC5363196
DOI:
10.1016/j.ymthe.2017.01.011
[Indexed for MEDLINE]
Free PMC Article

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