Research Images

Chimeric antigen receptor T-cell therapy targeting CD19 (CART-19) is
clinically active in pediatric B-cell acute lymphoblastic leukemia
(B-ALL), but loss of the CD19 epitope has been implicated in tumor
relapse. Sotillo and colleagues compared paired CD19-positive,
pre–CART-19 and CD19-negative, post–CART-19 relapsed pediatric B-ALL
samples and found hemizygous deletion of CD19 and mutations affecting
CD19 exon 2 in a subset of relapsed tumors. Alternatively spliced CD19
transcripts were also specifically identified in relapsed samples,
including a splice variant with exon 2 skipping (CD19 Δex2) that
resulted in expression of a functional truncated protein. CD19 Δex2
expression provided a proliferative advantage and partially rescued the
effects of CD19 loss. In addition, CD19 Δex2–expressing cells remained
viable upon CART-19 exposure, suggesting that alternative splicing can
lead to epitope loss and evasion from CAR T-cell therapy. For details,
please see the article by Sotillo and colleagues on page 1282.

Cover photograph: Four-channel confocal microscopy of a Nalm-6 B-ALL
cell engineered to express the immunotherapy-resistant CD19 exon 2
variant 105R. The corresponding CD19 protein is rendered in green and
shows colocalization with the endoplasmic reticulum marker calnexin
(magenta), as evidenced by the chromatic shift to white at the
colocalization sites. The plasma membrane is depicted in red (wheat germ
agglutinin), and the cell nucleus is counterstained with DAPI
(4′,6-diamidino-2-phenylindole; blue). The Adobe Photoshop craquelure
filter was applied to the image postoverlay. (See related article at
e00383-18.) (Copyright © 2018 American Society for Microbiology.