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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / immunology*
  • Apoptosis / genetics
  • Apoptosis / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Caspase 9 / metabolism*
  • Cell Proliferation
  • Cell Survival
  • Cytotoxicity, Immunologic*
  • Gene Expression
  • Gene Order
  • Genetic Vectors / genetics
  • Graft Survival
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Immunotherapy, Adoptive
  • Lymphocyte Activation / immunology
  • Mice
  • Molecular Imaging
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy
  • Protein Binding / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, CD19
  • CD19-specific chimeric antigen receptor
  • Receptors, Antigen, T-Cell
  • Caspase 9