Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-21168-6
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Funding
- Inserm, GIS IBiSA, Aix-Marseille Universite'
- Canceropole PACA
- Institut National du Cancer
- Region Sud
- European Union's Horizon 2020 research and innovation program under the Marie Skodowska-Curie Grant [713750]
- Regional Council of Provence-Alpes-Cote d'Azur, A*MIDEX [ANR-11-IDEX0001-02]
- ITMO Cancer of AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Sante, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan [C19046S]
- CNRS Osez l'interdisciplinarite! program-DMATh project
- [ANR-10-INBS-0009-10]
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The study demonstrates that CD19-negative leukemic subclones may already exist before CAR-T cell therapy in patients with B-ALL, leading to potential relapse. By utilizing single-cell RNA sequencing, pre-existing CD19 negative subclones were identified, highlighting the possibility of assessing the risk of targeted therapy failure.
Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19(neg)) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19(neg) leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19(neg) B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19(neg) subclones, raising the possibility to assess the risk of targeted therapy failure. CD19-negative relapses are observed in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 CAR-T cells. Here, by single-cell RNA sequencing of leukemic cells in a patient with B-ALL, the authors show that pre-existing CD19 negative leukemic subclones are present before CAR-T cell therapy and can account for the relapse.
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