Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
2015
The
CD19antigen, expressed on most
B-cell acute lymphoblastic leukemias(B-ALL), can be targeted with
chimeric antigen receptor–armed T cells (
CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the
CD19locus and de novo frameshift and missense mutations in exon 2 of
CD19in some relapse samples. However, we also discovered
alternatively spliced
CD19mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a
splicing factorinvolved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using
genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated
CD19variant, which fails to trigger killing by
CART-19 but partly rescues defects associated with
CD19loss. Thus, this mechanism of resistance is based on a combination of
deleterious mutationsand ensuing selection for
alternatively splicedRNA isoforms. Significance:
CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting
alternatively spliced
CD19isoforms with the compromised
CART-19 epitope. This mechanism suggests a possibility of targeting alternative
CD19
ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR . See related commentary by Jackson and Brentjens, [p. 1238][1] . This article is highlighted in the In This Issue feature, [p. 1225][2] [1]: /lookup/volpage/5/1238?iss=12 [2]: /lookup/volpage/5/1225?iss=12
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