The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration
Abstract
Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.
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“Lentiviral integrationmediated disruption of loci encoding genes mutated in CH has also been associated with cell-intrinsic alterations in CAR T cell expansion and differentiation [183][184][185] .”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [183]
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“Notably, knockdown of TET2 183 or knockout of DNMT3A 187 in experimental models of CAR T cells also led to increased differentiation of central memory CD8 + T cells and antitumour responses dependent on CAR stimulation (Fig. 3),”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [183]
In the citing paper
“suggesting that the effects TET2 disruption in CAR T cells were the result of biallelic impairment in TET2 function 183 .”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [183]
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Cites
High-Resolution Profiling of Histone Methylations in the Human Genome
Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., & Zhao, K. (2007) · Cell · doi:10.1016/j.cell.2007.05.009 · Cited by 6,845
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413 · cited 3×
“Confirming previous analyses (1, 4, 5), peak expansion was greater for CR/PRtd versus PR/NR (P = 0.”
Self-citationChimeric antigen receptor–modified T cells in chronic lymphoid leukemia
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A., & June, C. H. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103849 · Cited by 3,565
Self-citationLee, D. W., Kochenderfer, J. N., Stetler-Stevenson, M., Cui, Y. K., Delbrook, C., Feldman, S. A., Fry, T. J., Orentas, R., Sabatino, M., Shah, N. N., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61403-3 · Cited by 2,898
Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia
Davila, M. L., Rivière, I., Wang, X., Bartido, S. M., Park, J. H., Curran, K. J., Chung, S. S., Stefanski, J., Bórquez-Ojeda, O., Olszewska, M., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008226 · Cited by 2,514
Kalos, M., Levine, B. L., Porter, D. L., Katz, S., Grupp, S. A., Bagg, A., & June, C. H. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002842 · Cited by 2,388
Self-citationCombinatorial patterns of histone acetylations and methylations in the human genome
Wang, Z., Zang, C., Rosenfeld, J. A., Schones, D. E., Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Peng, W., Zhang, M. Q., et al. (2008) · Nature Genetics · doi:10.1038/ng.154 · Cited by 2,331
Age-related mutations associated with clonal hematopoietic expansion and malignancies
Xie, M., Lu, C., Wang, J., McLellan, M. D., Johnson, K. J., Wendl, M. C., McMichael, J. F., Schmidt, H. K., Yellapantula, V., Miller, C. A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3733 · Cited by 1,874
Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas
Schuster, S. J., Svoboda, J., Chong, E. A., Nasta, S. D., Mato, A. R., Anak, Ö., Brogdon, J. L., Pruteanu-Malinici, I., Bhoj, V., Landsburg, D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1708566 · Cited by 1,860
Self-citationInsertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1
Hacein-Bey-Abina, S., Garrigue, A., Wang, G. P., Soulier, J., Lim, A., Morillon, E., Clappier, E., Caccavelli, L., Delabesse, E., Beldjord, K., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35700 · Cited by 1,854
Self-citation
Cited by
Recent advances and discoveries in the mechanisms and functions of CAR T cells
Larson, R. C., & Maus, M. V. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00323-z · Cited by 852
Bai, Z., Woodhouse, S., Zhao, Z., Arya, R., Govek, K., Kim, D., Lundh, S., Baysoy, A., Sun, H., Deng, Y., et al. (2022) · Science Advances · doi:10.1126/sciadv.abj2820 · Cited by 166
Self-citationClonal haematopoiesis and dysregulation of the immune system
Belizaire, R., Wong, W. J., Robinette, M. L., & Ebert, B. L. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00843-3 · Cited by 161
Metadata
- Authors
- Nobles, C. L., Sherrill-Mix, S., Everett, J. K., Reddy, S., Fraietta, J. A., Porter, D. L., Frey, N., Gill, S. I., Grupp, S. A., Maude, S. L., Siegel, D. L., Levine, B. L., June, C. H., Lacey, S. F., Melenhorst, J. J., & Bushman, F. D.
- Venue
- Journal of Clinical Investigation
- Published
- 2019-12-17
- Volume
- 130
- Issue
- 2
- Pages
- 673-685
- ISSN
- 0021-9738
- 1558-8238
- Cited by
- 130
- References
- 73
- Language
- en
- Funders
- National Institutes of Health (T32 CA009140, P01 CA214278, P30 CA016520, R01 CA226983, K08 CA194256, R01 AI082020, R01 AI117950, P30 AI045008)
- Gabrielle’s Angel Foundation (--)
- PennCHOP Microbiome Program (--)
- Novartis Institute for Biomedical Research (000)
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- CoChat. (2026). Citation check: CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration. https://app.cochat.ai/papers/10.1172/jci130144
- The paper
- Nobles, C. L., Sherrill-Mix, S., Everett, J. K., Reddy, S., Fraietta, J. A., Porter, D. L., Frey, N., Gill, S. I., Grupp, S. A., Maude, S. L., Siegel, D. L., Levine, B. L., June, C. H., Lacey, S. F., Melenhorst, J. J., & Bushman, F. D. (2019). CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration. Journal of Clinical Investigation. https://doi.org/10.1172/jci130144
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
