ArticleCancer discovery2015
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy.
Article in Cancer discovery, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 805 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
805 citing papers in PubMed, 2 syntheses or guidelines pooled it, 1,229 citations in OpenAlex.
- Strategies and mechanisms for the enhancement of chimeric antigen receptor T-cell functions.Science China. Life sciences · 2026Pooled it
- Exploring current evidence on bispecific CAR-T cell therapy for acute leukemias: a systematic review.Frontiers in oncology · 2026Pooled it
- Bispecific CAR-T cells targeting CD19/20 in patients with relapsed or refractory B cell non-Hodgkin lymphoma: a phase I/II trial.Blood cancer journal · 2024Trial
- Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19Nature medicine · 2024Trial
- Oncolytic virus OVV-03 enhances CAR-T cell therapy against glioblastoma via immune modulation and specific HER2 upregulation.Oncoimmunology · 2026Article
- Tumor cell-intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer.Science advances · 2026Article
- Clinical Implications of CD19-Negative Relapse Following CD19-Directed Therapy in B-Cell Acute Lymphoblastic Leukemia.American journal of hematology · 2026Article
- RHOA Deletion Downregulates CD19 and Promotes Dysfunctional Immune Microenvironments in CAR-T Resistant Large B-cell Lymphomas.Blood cancer discovery · 2026Article
- Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions.Acta pharmacologica Sinica · 2026Review
- A genomic and epigenomic lens into the biology of acute lymphoblastic leukaemia.Nature reviews. Cancer · 2026Review
- Cancer cell-selective ectopic expression of CD20 as an antigen enables rituximab repurposing for solid tumour immunotherapy.Clinical and translational medicine · 2026Article
- Incorporating Immunotherapies into the Evolving Standard of Care for Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.Paediatric drugs · 2026Review
- Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy.Leukemia · 2026Article
- Review
- Antigen Pressure, Clonal Evolution, and Lineage Plasticity in B-Cell Acute Lymphoblastic Leukemia: Resistance Biology in the Immunotherapy Era.Current hematologic malignancy reports · 2026Review
- Alternative Splicing in Cyclin-Dependent Kinase 4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer.Drug development research · 2026Review
- FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia.Leukemia · 2026Article
- Article
- Mechanisms, optimization strategies, and salvage options for CAR-T cell therapy.Biomarker research · 2026Review
- Development of tandem canine CAR T cells to enable comparative studies of aggressive B-cell lymphoma.Molecular cancer therapeutics · 2026Article
745 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
30 authors at 2 institutions in 1 country.
Funding
Abstract
unlabelledThe 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.