{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:15:32Z","timestamp":1770286532184,"version":"3.49.0"},"reference-count":88,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-CA-241762-01"],"award-info":[{"award-number":["R01-CA-241762-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough in the treatment of relapsed and refractory B-cell malignancies, such as chronic lymphocytic leukemia (CLL), inducing long-term, sometimes curative, responses. However, fewer than 30% of CLL patients achieve such outcomes. It has been shown that a smaller subset of T cells capable of expansion and persistence is crucial for treatment effectiveness. Notably, a pre-existing mutation in the epigenetic regulator TET2, combined with CAR vector-induced disruption of the other intact allele, significantly enhanced the potency of the CAR-engineered T-cell clone in one CLL patient. This finding aligns with independent research, suggesting that the CAR gene\u2019s genomic insertion site influences tumor-targeting capability. Thus, it is plausible that vector-induced gene disruptions affect CAR T-cell function. This review synthesizes existing knowledge on vector integration into the host genome and its impact on clinical outcomes in CAR T-cell therapy patients. Our aim is to inform the development of improved therapies and enhance their overall efficacy.<\/jats:p>","DOI":"10.3390\/cancers17030383","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T05:24:31Z","timestamp":1737696271000},"page":"383","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Leveraging Vector-Based Gene Disruptions to Enhance CAR T-Cell Effectiveness"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7995-7996","authenticated-orcid":false,"given":"Beatriz C.","family":"Oliveira","sequence":"first","affiliation":[{"name":"Cell Therapy & Immuno-Engineering Program, Center for Immunotherapy and Precision Immuno-Oncology, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-8325","authenticated-orcid":false,"given":"Saaurav","family":"Bari","sequence":"additional","affiliation":[{"name":"Cell Therapy & Immuno-Engineering Program, Center for Immunotherapy and Precision Immuno-Oncology, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-537X","authenticated-orcid":false,"given":"J. Joseph","family":"Melenhorst","sequence":"additional","affiliation":[{"name":"Cell Therapy & Immuno-Engineering Program, Center for Immunotherapy and Precision Immuno-Oncology, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1200\/JCO.20.01467","article-title":"Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy","volume":"38","author":"Cappell","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s11684-021-0904-z","article-title":"CAR T-cell immunotherapy: A powerful weapon for fighting hematological B-cell malignancies","volume":"15","author":"Mi","year":"2021","journal-title":"Front. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s43018-021-00241-5","article-title":"Engineering enhanced CAR T-cells for improved cancer therapy","volume":"2","author":"Milone","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1056\/NEJMoa1407222","article-title":"Chimeric antigen receptor T cells for sustained remissions in leukemia","volume":"371","author":"Maude","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"95ra73","DOI":"10.1126\/scitranslmed.3002842","article-title":"T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia","volume":"3","author":"Kalos","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1172\/JCI85309","article-title":"CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients","volume":"126","author":"Turtle","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s43018-021-00207-7","article-title":"Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients","volume":"2","author":"Biasco","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1097\/CJI.0b013e3181ac6138","article-title":"Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor","volume":"32","author":"Kochenderfer","year":"2009","journal-title":"J. Immunother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10995","DOI":"10.1158\/0008-5472.CAN-06-0160","article-title":"CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells","volume":"66","author":"Kowolik","year":"2006","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1126\/science.1083413","article-title":"Transcription start regions in the human genome are favored targets for MLV integration","volume":"300","author":"Wu","year":"2003","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1172\/JCI35798","article-title":"Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients","volume":"118","author":"Howe","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.2174\/156652308786848021","article-title":"Mechanisms governing lentivirus integration site selection","volume":"8","author":"Ciuffi","year":"2008","journal-title":"Curr. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lewinski, M.K., Yamashita, M., Emerman, M., Ciuffi, A., Marshall, H., Crawford, G., Collins, F., Shinn, P., Leipzig, J., and Hannenhalli, S. (2006). Retroviral DNA integration: Viral and cellular determinants of target-site selection. PLoS Pathog., 2.","DOI":"10.1371\/journal.ppat.0020060"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1158\/2159-8290.CD-12-0548","article-title":"The basic principles of chimeric antigen receptor design","volume":"3","author":"Sadelain","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1038\/mt.2009.83","article-title":"Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo","volume":"17","author":"Milone","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41591-018-0010-1","article-title":"Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia","volume":"24","author":"Fraietta","year":"2018","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1200\/JCO.19.03237","article-title":"Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia","volume":"38","author":"Frey","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"303ra139","DOI":"10.1126\/scitranslmed.aac5415","article-title":"Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia","volume":"7","author":"Porter","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1182\/blood-2018-99-110462","article-title":"Rapid MRD-Negative Responses in Patients with Relapsed\/Refractory CLL Treated with Liso-Cel, a CD19-Directed CAR T-Cell Product: Preliminary Results from Transcend CLL 004, a Phase 1\/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib","volume":"132","author":"Siddiqi","year":"2018","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1200\/JCO.2014.56.2025","article-title":"Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor","volume":"33","author":"Kochenderfer","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1182\/blood.2019002936","article-title":"Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure","volume":"135","author":"Gauthier","year":"2020","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5774","DOI":"10.1182\/bloodadvances.2022007317","article-title":"Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia","volume":"6","author":"Gill","year":"2022","journal-title":"Blood Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1158\/2159-8290.CD-19-0813","article-title":"Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction","volume":"10","author":"Singh","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1038\/s41591-018-0146-z","article-title":"Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia","volume":"24","author":"Orlando","year":"2018","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1158\/2159-8290.CD-15-1020","article-title":"Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy","volume":"5","author":"Sotillo","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1038\/s41591-018-0201-9","article-title":"Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell","volume":"24","author":"Ruella","year":"2018","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41586-019-1054-1","article-title":"CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape","volume":"568","author":"Hamieh","year":"2019","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41467-019-13880-1","article-title":"Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy","volume":"11","author":"Sheih","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1182\/blood-2014-01-552174","article-title":"Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15","volume":"123","author":"Xu","year":"2014","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41586-021-04390-6","article-title":"Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells","volume":"602","author":"Melenhorst","year":"2022","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1172\/JCI130144","article-title":"CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration","volume":"130","author":"Nobles","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Labb\u00e9, R.P., Vessillier, S., and Rafiq, Q.A. (2021). Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives. Viruses, 13.","DOI":"10.3390\/v13081528"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nature15818","article-title":"Gene therapy returns to centre stage","volume":"526","author":"Naldini","year":"2015","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(02)00864-4","article-title":"HIV-1 integration in the human genome favors active genes and local hotspots","volume":"110","author":"Shinn","year":"2002","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1172\/JCI35700","article-title":"Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1","volume":"118","author":"Garrigue","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mitchell, R.S., Beitzel, B.F., Schroder, A.R., Shinn, P., Chen, H., Berry, C.C., Ecker, J.R., and Bushman, F.D. (2004). Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol., 2.","DOI":"10.1371\/journal.pbio.0020234"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1126\/science.1256304","article-title":"HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection","volume":"345","author":"Wagner","year":"2014","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1073\/pnas.1522675113","article-title":"Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo","volume":"113","author":"Simonetti","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1172\/JCI31659","article-title":"Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy","volume":"117","author":"Deichmann","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1038\/mt.2009.134","article-title":"Cell-intrinsic and vector-related properties cooperate to determine the incidence and consequences of insertional mutagenesis","volume":"17","author":"Kustikova","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10313","DOI":"10.1128\/JVI.01225-12","article-title":"HIV populations are large and accumulate high genetic diversity in a nonlinear fashion","volume":"87","author":"Maldarelli","year":"2013","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ymthe.2019.12.009","article-title":"Retroviral Insertional Mutagenesis in Humans: Evidence for Four Genetic Mechanisms Promoting Expansion of Cell Clones","volume":"28","author":"Bushman","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1056\/NEJM200301163480314","article-title":"A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency","volume":"348","author":"Schmidt","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1056\/NEJMoa1000164","article-title":"Efficacy of gene therapy for X-linked severe combined immunodeficiency","volume":"363","author":"Hauer","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/nature09328","article-title":"Transfusion independence and HMGA2 activation after gene therapy of human \u03b2-thalassaemia","volume":"467","author":"Payen","year":"2010","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1126\/science.288.5466.669","article-title":"Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease","volume":"288","author":"Gross","year":"2000","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/j.omtm.2020.04.016","article-title":"Vector Copy Distribution at a Single-Cell Level Enhances Analytical Characterization of Gene-Modified Cell Therapies","volume":"17","author":"Santeramo","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"133ra157","DOI":"10.1126\/scitranslmed.3003425","article-title":"Extended survival of glioblastoma patients after chemoprotective HSC gene therapy","volume":"4","author":"Adair","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41586-018-0178-z","article-title":"Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells","volume":"558","author":"Fraietta","year":"2018","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Jain, N., Zhao, Z., Iyer, A., Lopez, M., Feucht, J., Koche, R., Yang, J., Zhan, Y., and Sadelain, M. (and, January 10\u201315). Emergence of a hyper-proliferative phenotype in TET2 edited human CAR T cells. Proceedings of the American Association for Cancer Research Annual Meeting 2021, Philadelphia, PA, USA.","DOI":"10.1158\/1538-7445.AM2021-LB153"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Feng, Y., Li, X., Cassady, K., Zou, Z., and Zhang, X. (2019). TET2 Function in Hematopoietic Malignancies, Immune Regulation, and DNA Repair. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00210"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1182\/bloodadvances.2019000219","article-title":"Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy","volume":"3","author":"Shah","year":"2019","journal-title":"Blood Adv."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e006007","DOI":"10.1136\/jitc-2022-006007","article-title":"Targeting Cbl-b in cancer immunotherapy","volume":"11","author":"Augustin","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/35003235","article-title":"Cbl-b regulates the CD28 dependence of T-cell activation","volume":"403","author":"Chiang","year":"2000","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1084\/jem.20061699","article-title":"Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells","volume":"204","author":"Loeser","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/s41591-019-0549-5","article-title":"Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR","volume":"25","author":"Ghorashian","year":"2019","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1038\/s41375-018-0106-0","article-title":"Clinical use of lentiviral vectors","volume":"32","author":"Milone","year":"2018","journal-title":"Leukemia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00005-010-0063-4","article-title":"Lentiviral vectors in gene therapy: Their current status and future potential","volume":"58","author":"Escors","year":"2010","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"132ra153","DOI":"10.1126\/scitranslmed.3003761","article-title":"Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells","volume":"4","author":"Scholler","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ymthe.2017.10.012","article-title":"Retroviral and Lentiviral Safety Analysis of Gene-Modified T Cell Products and Infused HIV and Oncology Patients","volume":"26","author":"Marcucci","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ymthe.2017.09.008","article-title":"Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products","volume":"26","author":"Cornetta","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/mt.2011.288","article-title":"Replication-competent retroviruses in gene-modified T cells used in clinical trials: Is it time to revise the testing requirements?","volume":"20","author":"Bear","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1089\/hgtb.2012.175","article-title":"Evaluating a ligation-mediated PCR and pyrosequencing method for the detection of clonal contribution in polyclonal retrovirally transduced samples","volume":"24","author":"Brugman","year":"2013","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"14061","DOI":"10.1038\/mtm.2014.61","article-title":"High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies","volume":"2","author":"Giordano","year":"2015","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omto.2023.05.004","article-title":"Tagmentation-based analysis reveals the clonal behavior of CAR-T cells in association with lentivector integration sites","volume":"30","author":"Kim","year":"2023","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e72","DOI":"10.1093\/nar\/gkr140","article-title":"A method to sequence and quantify DNA integration for monitoring outcome in gene therapy","volume":"39","author":"Brady","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ebiom.2018.07.008","article-title":"Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR","volume":"34","author":"Hamada","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/nmeth.2688","article-title":"Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position","volume":"10","author":"Buenrostro","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.omtm.2020.10.012","article-title":"CReVIS-Seq: A highly accurate and multiplexable method for genome-wide mapping of lentiviral integration sites","volume":"20","author":"Kim","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ivan\u010di\u0107, D., Mir-Pedrol, J., Jaraba-Wallace, J., Rafel, N., Sanchez-Mejias, A., and G\u00fcell, M. (2022). INSERT-seq enables high-resolution mapping of genomically integrated DNA using Nanopore sequencing. Genome Biol., 23.","DOI":"10.1186\/s13059-022-02778-9"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1182\/blood.2021010858","article-title":"Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells","volume":"138","author":"Micklethwaite","year":"2021","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.jcyt.2023.01.005","article-title":"Engineered exosome-mediated messenger RNA and single-chain variable fragment delivery for human chimeric antigen receptor T-cell engineering","volume":"25","author":"Si","year":"2023","journal-title":"Cytotherapy"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1021\/acs.nanolett.9b04246","article-title":"Ionizable Lipid Nanoparticle-Mediated mRNA Delivery for Human CAR T Cell Engineering","volume":"20","author":"Billingsley","year":"2020","journal-title":"Nano Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6080","DOI":"10.1038\/s41467-020-19486-2","article-title":"In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo","volume":"11","author":"Parayath","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/s41375-020-0951-5","article-title":"Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma","volume":"35","author":"Lin","year":"2021","journal-title":"Leukemia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2217\/imt-2021-0143","article-title":"A CD123-specific chimeric antigen receptor augments anti-acute myeloid leukemia activity of V\u03b39V\u03b42 T cells","volume":"14","author":"Zhang","year":"2022","journal-title":"Immunotherapy"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.5114\/aoms.2019.84888","article-title":"Mesothelin-targeted CAR-T cells for adoptive cell therapy of solid tumors","volume":"17","author":"Zhang","year":"2021","journal-title":"Arch. Med. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1126\/science.abm0594","article-title":"CAR T cells produced in vivo to treat cardiac injury","volume":"375","author":"Rurik","year":"2022","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.tibtech.2023.08.005","article-title":"Chimeric antigen receptor therapy meets mRNA technology","volume":"42","author":"Wu","year":"2024","journal-title":"Trends Biotechnol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1186\/s12967-024-05957-3","article-title":"From bench to bedside: Cutting-edge applications of base editing and prime editing in precision medicine","volume":"22","author":"Xu","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/s41587-020-0561-9","article-title":"Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors","volume":"38","author":"Anzalone","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1038\/s41375-024-02444-y","article-title":"Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy","volume":"38","author":"Lei","year":"2024","journal-title":"Leukemia"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Antoniou, P., Miccio, A., and Brusson, M. (2021). Base and Prime Editing Technologies for Blood Disorders. Front. Genome Ed., 3.","DOI":"10.3389\/fgeed.2021.618406"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.tibtech.2023.03.004","article-title":"Prime editing: Advances and therapeutic applications","volume":"41","author":"Zhao","year":"2023","journal-title":"Trends Biotechnol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Vitale, C., and Strati, P. (2020). CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00849"},{"key":"ref_86","unstructured":"FDA (2025, January 18). FDA Investigating Serious Risk of T-Cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T Cell Immunotherapies, Available online: https:\/\/www.fda.gov\/vaccines-blood-biologics\/safety-availability-biologics\/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/s41591-024-02826-w","article-title":"T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy","volume":"30","author":"Ghilardi","year":"2024","journal-title":"Nat. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1056\/NEJMoa2401530","article-title":"Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy","volume":"390","author":"Ozdemirli","year":"2024","journal-title":"N. Engl. J. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/383\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:35:20Z","timestamp":1759919720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/383"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":88,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cancers17030383"],"URL":"https:\/\/doi.org\/10.3390\/cancers17030383","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]}}}