CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration.

Autor:	Nobles CL; Department of Microbiology., Sherrill-Mix S; Department of Microbiology., Everett JK; Department of Microbiology., Reddy S; Department of Microbiology., Fraietta JA; Department of Microbiology.; Center for Cellular Immunotherapies.; Department of Pathology and Laboratory Medicine, and.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Porter DL; Center for Cellular Immunotherapies.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Frey N; Center for Cellular Immunotherapies.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Gill SI; Center for Cellular Immunotherapies.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Grupp SA; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Maude SL; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Siegel DL; Center for Cellular Immunotherapies.; Department of Pathology and Laboratory Medicine, and., Levine BL; Center for Cellular Immunotherapies.; Department of Pathology and Laboratory Medicine, and.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., June CH; Center for Cellular Immunotherapies.; Department of Pathology and Laboratory Medicine, and.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lacey SF; Center for Cellular Immunotherapies.; Department of Pathology and Laboratory Medicine, and.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Melenhorst JJ; Center for Cellular Immunotherapies.; Department of Pathology and Laboratory Medicine, and.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Bushman FD; Department of Microbiology.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Feb 03; Vol. 130 (2), pp. 673-685.
DOI:	10.1172/JCI130144
Abstrakt:	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.
Databáze:	MEDLINE
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