Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
By Elena Sotillo, D. Barrett, K. Black, A. Bagashev, D. Oldridge, Glendon S. Wu, Robyn T. Sussman, Claudia B. Lanauze, M. Ruella, Matthew R. Gazzara and 20 more. Cancer Discovery, 2015
1,165 citations recorded by the source corpus.
The CD19 antigen, 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 CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved 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 CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA 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 CD19 isoforms 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.
Subfields: Molecular Biology, Oncology, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/268ce0cec92273cccf952938159af6d3d67486fc
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Citations in the corpus
- Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. (2016, background): “The karyotype was 46,XX,t(4;11)(q21;q23),add(9)(p12)[cp20], and FISH studies showed that 83.”
- Engineered T cells: the promise and challenges of cancer immunotherapy (2016, background): “Crosstalk between ROR1 and the pre-B cell receptor promotes survival of t(1;19) acute lymphoblastic leukemia.”
- CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment (2019, background): “With the optimization of gene editing methods, CRISPR/Cas9 edited CARs are already moving into clinical trials: a PD-1 knockout CD19 CAR has is being studied in a phase I clinical trial (NCT03298828).”
- CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. (2016, neutral): “Leukemia relapse after CAR–T cells could be classified into 2 distinct phenotypes: those with loss of the CD19 target antigen as observed by others (25) and those that remained CD19+ and relapsed in a manner associated with loss of CD19 CAR–T cells in blood.”
- Tumor Antigen Escape from CAR T-cell Therapy. (2018, background): “Immune pressure by the CD19 CAR results in selection of leukemia cells expressing higher proportions of these splice variants, leading to escape from detection by CD19 CAR T cells (32).”
- CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL (2017, neutral): “…following CD19 directed immunotherapy due to preferential expression of CD19 splice variants in resistant leukemia lacking the targeted epitope 16 , we observed a pattern of acquired resistance to CD22-CAR associated with diminished (Figure 3) and variable (Supplemental Figure 3) CD22 site…”