Article ; Online: Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.
2023 Volume 29, Issue 7, Page(s) 1700–1709
Abstract: In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, ...
| Abstract | In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists. |
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| MeSH term(s) | Humans ; Antigens, CD19/genetics ; Immunotherapy, Adoptive ; Leukemia, Lymphocytic, Chronic, B-Cell ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Receptors, Antigen, T-Cell ; Remission Induction ; T-Lymphocytes |
| Chemical Substances | Antigens, CD19 ; Receptors, Antigen, T-Cell ; CD19 molecule, human |
| Language | English |
| Publishing date | 2023-07-06 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1220066-9 |
| ISSN | 1546-170X ; 1078-8956 |
| ISSN (online) | 1546-170X |
| ISSN | 1078-8956 |
| DOI | 10.1038/s41591-023-02415-3 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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