Editors' ChoiceCancer

Self-defeating CAR-Ts protect leukemic cells

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Science Translational Medicine  17 Oct 2018:
Vol. 10, Issue 463, eaav3888
DOI: 10.1126/scitranslmed.aav3888

Abstract

Transfer of a CAR gene to a leukemic cell confers resistance to CAR-T cell therapy.

Chimeric antigen receptor (CAR)–T cell therapy is an exciting new treatment for B cell malignancies. It is based on the systemic administration of T cells that have been genetically engineered with a CAR—a designer receptor that targets a tumor antigen through an antibody-like domain and signals internally through a T cell receptor–like domain. Infusion of these cells can be highly effective in some patients but ineffective in others, and the mechanisms of treatment failure, though increasingly understood, are not fully elucidated.

A recent paper by Ruella et al. reveals a new and important mechanism of CAR-T cell failure. The authors studied a patient with CD19+ B cell acute lymphoblastic leukemia who received CD19 CAR-T cell therapy and experienced a complete clinical response followed by relapse. At relapse, the leukemic cells were found to express the CD19 CAR, which was unintentionally transduced into one of these cells during cell product manufacturing. Interestingly, the extracellular domain of the CD19 molecule was not detectable in the CAR-transduced leukemic cells by flow cytometry. However, the CD19 intracellular region was detectable by flow cytometry, and the CD19 molecule colocalized with the CD19 CAR by confocal microscopy. These results were explained by the finding that binding of the CD19+ extracellular domain of leukemic cells by the CD19 CAR on the same cells “masked” the CAR’s target epitope, rendering the leukemia resistant to CD19 CAR-T cells. The masking phenomenon was also reproduced with CD22 CAR-T cells in CD22+ tumor cell lines in vitro, indicating that it may be generalizable. However, study of other patients treated with CD19 CAR therapy suggested that the phenomenon is unusual.

These findings reveal an interesting mechanism of CAR-T cell treatment failure that is not related to the T cells or to canonical acquired tumor resistance but rather to the preventable introduction of resistance during cell manufacturing. They show the underappreciated importance of eliminating all leukemic cells from the T cell product prior to CAR genetic engineering.

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