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Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells
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“Further, in a recent phase I trial, lymphoma arising from piggyBac transfected CAR T cells has been reported in two of nine patients with relapsed or refractory B-cell malignancies who achieved complete remission after product infusion.”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [107]
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Cited by
Sorted by citations
CAR T therapy beyond cancer: the evolution of a living drug
Baker, D. J., Arany, Z. P., Baur, J. A., Epstein, J. A., & June, C. H. (2023) · Nature · doi:10.1038/s41586-023-06243-w · Cited by 546
Hayden, P. J., Roddie, C., Bader, P., Basak, G. W., Bonig, H. B., Bonini, C., Chabannon, C., Ciceri, F., Corbacioglu, S., Ellard, R., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.12.003 · Cited by 486
From bench to bedside: the history and progress of CAR T cell therapy
Mitra, A., Barua, A., Huang, L., Ganguly, S., Feng, Q. F., & He, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1188049 · Cited by 526
Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy
Abou-el-Enein, M., Elsallab, M., Feldman, S. A., Fesnak, A. D., Heslop, H. E., Marks, P., Till, B. G., Bauer, G., & Savoldo, B. (2021) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0084 · Cited by 321
“The analysis of the lymphoma samples showed an increase in the transgene copy numbers but with no integration in typical oncogenes (107, 108).”
BackgroundCAR-T cell manufacturing: Major process parameters and next-generation strategies
Ceja, M. A., Khericha, M., Harris, C. M., Puig-Saus, C., & Chen, Y. Y. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20230903 · Cited by 349
“In a phase 1 clinical trial, two patients treated with allogeneic CD19 CAR-T cell products generated with the piggyBac transposon system developed CAR-T cell – derived lymphoma, resulting in one fatality (Bishop et al., 2021).”
BackgroundCurrent understanding and management of CAR T cell-associated toxicities
Brudno, J. N., & Kochenderfer, J. N. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00903-0 · Cited by 352
“…cell-derived malignancies, CAR + T cell lymphoma occurred in two patients who received investigational allogeneic, donor-derived CD19-directed CAR T cells genetically modified using a PiggyBac transposon system; however, no integration of the transgene into known oncogenes was identified 151,152 .”
T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy
Ghilardi, G., Fraietta, J., Gerson, J., Deerlin, V. V., Morrissette, J. J. D., Caponetti, G. C., Paruzzo, L., Harris, J., Chong, E. A., Susanibar-Adaniya, S., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02826-w · Cited by 249
“In both cases, the post-CAR T TCL progressed and resulted in the death of one of the patients, whereas the other patient successfully received an allogeneic transplant 20,21 .”
Micklethwaite, K. P., Gowrishankar, K., Gloss, B. S., Li, Z., Street, J. A., Moezzi, L., Mach, M. A., Sutrave, G., Clancy, L. E., Bishop, D. C., et al. (2021) · Blood · doi:10.1182/blood.2021010858 · Cited by 226
Self-citationOttaviano, G., Georgiadis, C., Gkazi, S. A., Syed, F., Zhan, H., Etuk, A., Preece, R., Chu, J., Kubat, A., Adams, S. P., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abq3010 · Cited by 212
Kok, N., Panella, D., Georgoudaki, A., Liu, H., Özkazanç, D., Kučerová, L., Duru, A. D., Spanholtz, J., & Raimo, M. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01382-5 · Cited by 191
“Transposons have been used in CAR-T setting [159, 160]; however, CAR-T cell lymphoma was developed by patients treated with piggyBac-modified cells [160], possibly related to insertional oncogenesis, where a high vector copy number was found in one of such patients [161].”
NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma
Leivas, A., Valeri, A., Córdoba, L., García-Ortiz, A., Ortiz, A., Sánchez-Vega, L., Graña-Castro, O., Fernández, L., Carreño-Tarragona, G., Pérez, M., et al. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00537-w · Cited by 139
“Transposon constructs are an interesting strategy [51]; however, two cases of CAR-positive lymphoma have recently been reported [52].”
BackgroundBispecific antibodies and CAR-T cells: dueling immunotherapies for large B-cell lymphomas
Trabolsi, A., Arumov, A., & Schatz, J. H. (2024) · Blood Cancer Journal · doi:10.1038/s41408-024-00997-w · Cited by 123
“Experimental use of the piggyBac retrotransposon system to generate CD19 CAR-T cells resulted in 2 of 10 patients developing CAR-positive lymphomas [48], but this system is not used in the manufacture of any FDA-approved CAR product.”
MethodPrecision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms
Michels, A., Ho, N., & Buchholz, C. J. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.05.018 · Cited by 131
“In contrast to LVs, transposonmediated gene transfer had its “SCID moment” last year, when two patients receiving CAR T cells generated ex vivo using piggyBac transposase developed T cell lymphoma.(107,108) Although themechanism of oncogenesis is still under investigation, this incident must lead to development of saf…”
Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond
Bittner, S., Hehlgans, T., & Feuerer, M. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.04.005 · Cited by 110
CAR-NK cell therapy: promise and challenges in solid tumors
Balkhi, S., Zuccolotto, G., Spirito, A. D., Rosato, A., & Mortara, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1574742 · Cited by 101
Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy
Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2401361 · Cited by 223
“Our results are in contrast with rare prior reports using other therapeutic vectors including transposons 13,14 .”
Irving, M. B., Lanitis, E., Migliorini, D., Ivics, Z., & Guedan, S. (2021) · Human Gene Therapy · doi:10.1089/hum.2021.173 · Cited by 112
“Following CAR-T cell infusion, two patients developed T cell lymphoma leading to the death of one of the patients.(49,50)”
BackgroundCell and gene therapy for kidney disease
Peek, J. L., & Wilson, M. H. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00702-3 · Cited by 86
Tipanee, J., Samara-Kuko, E., Gevaert, T., Chuah, M. K., & VandenDriessche, T. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.06.006 · Cited by 76
Non-viral chimeric antigen receptor (CAR) T cells going viral
Balke‐Want, H., Keerthi, V., Cadiñanos-Garai, A., Fowler, C., Gkitsas-Long, N., Brown, A. K., Tunuguntla, R. H., Abou‐El‐Enein, M., & Feldman, S. A. (2023) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2023.100375 · Cited by 75
“As such, there is a need for better preclinical genotoxicity models and optimization strategies.(28,40) CRISPR-associated transposons, which offer guided transposition and improved genotoxicity profiles, are emerging as a promising alternative.”
BackgroundHu, Y., Zu, C., Zhang, M., Wei, G., Li, W., Fu, S., Hong, R., Zhou, L., Wu, W., Cui, J., et al. (2023) · EClinicalMedicine · doi:10.1016/j.eclinm.2023.102010 · Cited by 68
Hiltensperger, M., & Krackhardt, A. M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1121030 · Cited by 79
“Although PB transposition was also successful for the manufacturing of CAR-T cells and even showed an inclination to promote the generation of desired TSCM CAR-T cells (66, 67), a recent clinical trial observed the formation of CAR-T cell lymphoma in two out of ten patients (68, 69).”
ResultEngineering strategies to safely drive CAR T-cells into the future
Rossi, M., & Breman, E. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1411393 · Cited by 68
Madison, B., Patil, D. P., Richter, M., Li, X., Tong, M., Cranert, S. A., Wang, X., Martin, R. M., Xi, H., Tan, Y., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.06.003 · Cited by 61
“However, this event was likely not driven by classical insertional mutagenesis, as concluded by the authors themselves.(52,53) Rather, contributing factors likely included process-related parameters, such as DNA-damaging high-voltage electroporation conditions, and patient-specific exacerbating conditions, such as GVH…”
BackgroundWagner, D. L., Koehl, U., Chmielewski, M. M., Scheid, C., & Stripecke, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.865424 · Cited by 65
Future perspectives on engineered T cells for cancer
Posey, A. D., Young, R. M., & June, C. H. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.05.007 · Cited by 58
Ruppel, K. E., Fricke, S., Koehl, U., & Schmiedel, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.822298 · Cited by 53
Wang, M., Krueger, J. B., Gilkey, A. K., Stelljes, E. M., Kluesner, M. G., Pomeroy, E. J., Skeate, J. G., Slipek, N. J., Lahr, W. S., Claudio Vázquez, P. N., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009560 · Cited by 45
NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development
Dezfouli, A. B., Yazdi, M., Pockley, A. G., Khosravi, M., Kobold, S., Wagner, E., & Multhoff, G. (2021) · Cells · doi:10.3390/cells10123390 · Cited by 53
Golikova, E., Alshevskaya, A., Alrhmoun, S., Sivitskaya, N. A., & Sennikov, S. V. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05703-9 · Cited by 50
“The PiggyBac (PB) system was also successfully used to generate CAR-T cells [126], but later trials reported cases of CAR-T cell lymphoma [127, 128].”
MethodBalke-Want, H., Keerthi, V., Gkitsas, N., Mancini, A., Kurgan, G., Fowler, C., Xu, P., Liu, X.-K., Asano, K., Patel, S., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01799-7 · Cited by 41
Aggressive Lymphoma after CD19 CAR T-Cell Therapy
Kobbe, G., Brüggemann, M., Baermann, B., Wiegand, L., Trautmann, H., Yousefian, S., Libertini, S., Menssen, H. D., Maier, H. J., Ulrich, P. C., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2402730 · Cited by 60
Louie, R. H. Y., Cai, C., Samir, J., Singh, M., Deveson, I. W., Ferguson, J. M., Amos, T. G., McGuire, H. M., Gowrishankar, K., Adikari, T. N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43656-7 · Cited by 38
“In this study, we analyse eight patients who received donor-derived piggyBac-modi fi ed CD19 CAR T cells 28 .”
InfluentialSelf-citationDonor T cells for CAR T cell therapy
Tang, T. C. Y., Xu, N., Nordon, R. E., Haber, M., Micklethwaite, K. P., & Dolnikov, A. (2022) · Biomarker Research · doi:10.1186/s40364-022-00359-3 · Cited by 43
“Recent Phase I clinical trial (ACTRN12617001579381) data showed 9 out of 10 patients achieving complete remission after treatment with donor-derived piggyBac transposonbased CAR19T cells against r/r B-ALL or aggressive lymphoma post-HSCT; however, 2 patients developed malignant CAR19T cell-derived lymphoma that result…”
BackgroundSelf-citationOttaviano, G., & Qasim, W. (2025) · Leukemia · doi:10.1038/s41375-025-02585-8 · Cited by 45
“New-onset T cell lymphomas were reported in two patients receiving engineered T cells using PiggyBac transposons for expression of CAR19 [85].”
Efficient non-viral CAR-T cell generation via silicon-nanotube-mediated transfection
Chen, Y.-P., Mach, M., Shokouhi, A., Yoh, H., Bishop, D., Murayama, T., Suu, K., Morikawa, Y., Barry, S., Micklethwaite, K., et al. (2023) · Materials Today · doi:10.1016/j.mattod.2023.02.009 · Cited by 35
Self-citationMcErlean, E. M., & McCarthy, H. O. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02746-4 · Cited by 42
Current Non-Viral-Based Strategies to Manufacture CAR-T Cells
Gehrke, L., Gonçalves, V. D. R., Andrae, D., Raskó, T., Ho, P., Einsele, H., Hudecek, M., & Friedel, S. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413685 · Cited by 34
“If this occurs, especially within proto-oncogenes or tumor-suppressor genes, malignant transformation of CAR-T cells could be observed [63,160].”
Yao, P., Liu, Y., Huang, G., Hao, L., & Wang, R. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00583-7 · Cited by 33
Buechner, J., Caruana, I., Künkele, A., Rives, S., Vettenranta, K. K., Bader, P., Peters, C., Baruchel, A., & Calkoen, F. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2021.784024 · Cited by 32
“Even though all three techniques are commonly used to generate autologous and allogeneic clinical-grade CAR products, recent evidence stresses a point of caution regarding the oncogenic potential of transposon systems (piggyBacs) with the first 2 cases of malignant lymphoma derived from CAR genetically modified T cell…”
BackgroundFocusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy
Zhang, S., Peng, L., Chen, Y., Yan, X., & Moradi, V. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00358-x · Cited by 35
Activation-inducible CAR expression enables precise control over engineered CAR T cell function
Fräßle, S. P., Tschulik, C., Effenberger, M. J. P., Cletiu, V., Gerget, M., Schober, K., Busch, D. H., Germeroth, L., Stemberger, C., & Poltorak, M. P. (2023) · Communications Biology · doi:10.1038/s42003-023-04978-w · Cited by 30
Abken, H. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01062-y · Cited by 32
Gazeau, N., Beauvais, D., Tilmont, R., Srour, M., Ferrant, E., Safar, V., Fouillet, L., Flandrin-Gresta, P., Gower, N., Chauvet, P., et al. (2025) · Leukemia · doi:10.1038/s41375-025-02605-7 · Cited by 24
Long‐term survivorship care after CAR‐T cell therapy
Puckrin, R., Jamani, K., & Jimenez-Zepeda, V. H. (2023) · European Journal Of Haematology · doi:10.1111/ejh.14100 · Cited by 26
“96,97 To our knowledge, such occurrences of malignant transformation have not been described with other CAR-T cell products, but cases of clonal CAR-T cell expansion have been reported due to lentiviral integration into recipient BCL or TET2 genes.”
BackgroundBerg, P., Bakker, C., Sander, M., Lundstrøm, N. H., Erneholm, K., Musuamba-Tshinanu, F., Kholmanshikh, O., Nuffel, F. V., Müller, S., Ruppert-Seipp, G., et al. (2025) · Gene Therapy · doi:10.1038/s41434-025-00586-x · Cited by 23
“Some of these and other individual case reports of patients developing a T-cell malignancy after receiving CAR T-cell therapy have been published [9 – 14].”
iPS cell therapy 2.0: Preparing for next‐generation regenerative medicine
Hui, K. K., & Yamanaka, S. (2024) · BioEssays · doi:10.1002/bies.202400072 · Cited by 23
“[27,28] Thus, in addition to a desire for fine regulation of the cellular activities of iPSC-derived cells, the next iteration of iPSC-based therapies should inertsmallmolecule,AP1903,inducesthedimerizationofthismodified caspase-9, thus activating the intrinsic pathway of apoptosis to elicit…”
Universal CAR 2.0 to overcome current limitations in CAR therapy
Schlegel, L. S., Werbrouck, C., Boettcher, M., & Schlegel, P. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1383894 · Cited by 21
Zhou, Z., Chen, Y., Ba, Y., Xu, H., Zuo, A., Liu, S., Zhang, Y., Weng, S., Ren, Y., Luo, P., et al. (2024) · Cell Proliferation · doi:10.1111/cpr.13791 · Cited by 20
Answering the “Doctor, can CAR-T therapy cause cancer?” question in clinic
Banerjee, R. K., Poh, C., Hirayama, A. V. V., Gauthier, J., Cassaday, R. D., Shadman, M. S., Cowan, A. J., Till, B. G., Green, D. J., Kiem, H., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2023012336 · Cited by 22
“31 Subsequent analyses implicated high transgene copy numbers per cell rather than CAR insertion as a key factor associated with oncogenesis.”
BackgroundWebber, B. R., Johnson, M. J., Skeate, J. G., Slipek, N. J., Lahr, W. S., DeFeo, A. P., Mills, L. J., Qiu, X., Rathmann, B., Diers, M. D., et al. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01157-4 · Cited by 29
Gene knockout in cellular immunotherapy: Application and limitations
Zhang, X., Jin, X. K., Sun, R., Zhang, M., Lu, W., & Zhao, M. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215736 · Cited by 22
Current state of CAR-T cell therapies for solid tumors
Rosa, R. C. A., Liu, J., Lu, C., Abou‐El‐Enein, M., Murad, J. P., & Priceman, S. J. (2026) · Med · doi:10.1016/j.medj.2026.101028 · Cited by 21
BCMA-directed therapy, new treatments in the myeloma toolbox, and how to use them
Rees, M. J., & Kumar, S. K. (2023) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2023.2284088 · Cited by 22
“A theoretical risk of t-cell lymphoma exists from the use of viral vector-based gene integration disrupting oncogenes or tumor suppressor genes, and there have been two such cases of cARt cell lymphoma, in cells manufactured with the piggyBac transposon system [61].”
BackgroundLong-term follow-up of CD19-CAR T-cell therapy in children and young adults with B-ALL.
Epperly, R., & Shah, N. (2023) · Hematology. American Society of Hematology. Education Program · doi:10.1182/hematology.2023000422 · Cited by 18
Chen, S.-F., Zhang, Y., Fang, C.-L., Zhang, N.-Q., Wang, Y., Chen, R., Li, Y., & Tu, S. (2022) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2022.103807 · Cited by 18
CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts
Berg, P., Ruppert‐Seipp, G., Müller, S., Maurer, G. D., Hartmann, J., Holtick, U., Buchholz, C. J., & Funk, M. B. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00183-2 · Cited by 20
“The development of a CAR-positive T-cell lymphoma was recently described following administration of CD19 CAR T cells generated using a nonviral piggyBac transposon system (Bishop et al, 2021; Micklethwaite et al, 2021).”
Clinical development of allogeneic chimeric antigen receptor αβ-T cells
Georgiadis, C., Preece, R., & Qasim, W. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.040 · Cited by 17
“123,124 Allogeneic products should in theory not be at such a heightened risk of carrying predisposing changes, but as engineering steps become more sophisticated, with multiple changes being applied, diligent monitoring will be required.”
Camacho-Arteaga, L., Iacoboni, G., Kwon, M., Bailén, R., Hernani, R., Benzaquén, A., López-Corral, L., Pérez-López, E., Leguízamo-Martínez, L. M., Calvo-Orteu, M., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2024.61683 · Cited by 15
Bouziana, S. D., & Bouzianas, D. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179518 · Cited by 12
“The lymphomagenesis was related to high transgene insertion copy numbers, but it was thought that the widespread genomic copy number variations found within the genome of lymphoma cells was the dominant driver of carcinogenesis [30,82].”
BackgroundGupta, A. O., Azul, M., Bhoopalan, S. V., Abraham, A., Bertaina, A., Bidgoli, A., Bonfim, C., Dezern, A. E., Li, J., Louis, C. U., et al. (2024) · Cytotherapy · doi:10.1016/j.jcyt.2024.06.002 · Cited by 17
piggyBac-transposon-mediated CAR-T cells for the treatment of hematological and solid malignancies
Yagyu, S., & Nakazawa, Y. (2023) · International Journal of Clinical Oncology · doi:10.1007/s10147-023-02319-9 · Cited by 15
“Although a recent clinical trial [47] highlighted a safety concern of CAR-T cell-derived lymphoma, piggyBac CAR-T cells remain an attractive method to improve the efficacy of CAR-T cell therapy.”
BackgroundMethodChimeric Antigen Receptor Based Cellular Therapy for Treatment Of T-Cell Malignancies
Polgárová, K., Otáhal, P., Šálek, C., & Pytlík, R. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.876758 · Cited by 19
Allogeneic Chimeric Antigen Receptor Therapy in Lymphoma
Khurana, A., & Lin, Y. (2022) · Current Treatment Options in Oncology · doi:10.1007/s11864-021-00920-6 · Cited by 17
CAR T treatment beyond cancer: Hope for immunomodulatory therapy of non-cancerous diseases
Yang, Z., Liu, Y., & Hai, Z. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122556 · Cited by 16
INSERT-seq enables high-resolution mapping of genomically integrated DNA using Nanopore sequencing
Ivančić, D., Mir-Pedrol, J., Jaraba-Wallace, J., Rafel, N., Sánchez-Mejías, A., & Güell, M. (2022) · Genome biology · doi:10.1186/s13059-022-02778-9 · Cited by 22
“such as the PiggyBac transposase (PB) have been linked to oncogenic induction [11].”
BackgroundDhakal, B., Chhabra, S., Savani, B. N., & Hamadani, M. (2021) · British Journal of Haematology · doi:10.1111/bjh.17904 · Cited by 14
“Investigators at the Memorial Sloan Kettering Cancer Center have employed CRISPR/Cas9 to target an anti-CD19 CAR T cell to the TRAC locus, which resulted in uniform CAR expression in T cells, with substantially lower risks of both insertional oncogenesis and GVHD, and with enhanced T-cell potency.58 Bishop et al.87 ge…”
MethodMechanisms of Resistance to CAR T-Cells and How to Overcome Them
Legato, L., Bisio, M., Fasano, F., Savelli, C. B., Secreto, C., Dellacasa, C. M., Botto, B., Busca, A., Cerrano, M., Freilone, R., et al. (2025) · Methods and Protocols · doi:10.3390/mps8050108 · Cited by 14
“However, concerns have been raised regarding potential insertional mutagenesis, especially with piggyBac, which has been associated with integration near oncogenes and rare cases of lymphomagenesis [118,119].”
Harnessing the Immune System to Fight Multiple Myeloma
Krejcik, J., Barnkob, M. B., Nyvold, C. G., Larsen, T. S., Barington, T., & Abildgaard, N. (2021) · Cancers · doi:10.3390/cancers13184546 · Cited by 16
“The importance of choosing a safe method for gene transfer is highlighted by a recent reporting of development of CAR T-cell-derived lymphoma in two of ten patients effectively treated with piggyBac modified CD19-specific CAR T-cells [86].”
MethodKozani, P. S., & Kozani, P. S. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07183-x · Cited by 13
“Transcriptional dysregulation was associated with these genomic alterations [77, 78].”
Assessing the oncogenic risk: the long-term safety of autologous chimeric antigen receptor T cells.
Baker, D. J., Levine, B. L., & June, C. H. (2025) · The Lancet · doi:10.1016/s0140-6736(25)00039-x · Cited by 12
RNA-loaded nanoparticles for the treatment of hematological cancers
Garbayo, E., Moukhtari, S. H. E., Rodríguez‐Nogales, C., Agirre, X., Rodríguez-Madoz, J. R., Rodríguez-Márquez, P., Prósper, F., Couvreur, P., & Blanco‐Prieto, M. J. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115448 · Cited by 19
Niu, A., Zou, J., Hu, X., Zhang, Z., Su, L., Wang, J., Xing, L., Zhang, W., Chen, W., & Zhang, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1068625 · Cited by 12
“In comparison to the safety of lentiviral/retroviral systems observed in a cohort of 308 patients (16), a recent clinical trial on PB CAR-T-cell lymphoma reported a concerning oncogenic effect of transposon gene integration system (42).”
Banihashemi, S. R., Rahbarizadeh, F., Zavaran-Hosseini, A., Ahmadvand, D., & Nikkhoi, S. K. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107927 · Cited by 12
Expression of membrane-bound Interleukin-15 sustains the growth and survival of CAR-NK cells.
Feng, D., Sun, L., Hu, D., Wu, J., Xu, F., Kong, X., Yang, R., Jiang, G., Jiang, L.-H., Wang, S., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115577 · Cited by 11
Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma
Cordeiro, A. C., Durisek, G., Batista, M., Schmidt, J., Lima, M. D. D., & Bezerra, E. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1404351 · Cited by 11
“There were two cases of CART-derived T-cell malignancy among 10 patients treated with an investigational CART product manufactured by piggyback, a non-viral technology (80).”
BackgroundLemmens, M., Dorsheimer, L., Zeller, A., & Dietz, Y. (2024) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2024.503767 · Cited by 15
Multimodal cell-cell communication driving CD8+ T cell dysfunction and immune evasion
Chen, L., Huang, Q., & Zhou, P. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1691746 · Cited by 8
Fine tuning towards the next generation of engineered T cells
Nguyen, T. T., Ho, P., Staudt, S., Grégoire, C., Ziegler-Martin, K., Jassin, M., Block, A., Hudecek, M., Melenhorst, J. J., Caers, J., et al. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01492-8 · Cited by 11
“Furthermore, recent cases of rare malignant transformation by administered CAR T cell products have raised an awareness for potential genotoxic events asking for safety profiling and measures in the future, especially in light of multiplex-edited strategies 182,197 .”
Jain, M. D., Abramson, J. S., & Ansell, S. M. (2025) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk-25-473916 · Cited by 11
DNA transposon mechanisms and pathways of genotoxicity
Bushman, F. D. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.01.023 · Cited by 12
Phase I CAR-T Clinical Trials Review
Bulsara, S., Wu, M.-F., & Wang, T. (2022) · Anticancer Research · doi:10.21873/anticanres.16076 · Cited by 11
Natural killer cells in adoptive cell therapy: current landscape of genetic engineering strategies
Burón, M., Etxebarria, A., Álvarez, M., Romayor, I., & Eguizábal, C. (2025) · OncoImmunology · doi:10.1080/2162402x.2025.2563099 · Cited by 10
“104,105 Finally, Tol2 was the first vertebrate transposable element discovered in medaka fish and it has been extensively used to generate transgenic animals, especially in zebrafish model.”
Engineering strategies to mitigate toxicities associated with CAR‐T cell therapy
Wolter, T., Wang, Y., & Hu, Q. (2024) · BMEMat · doi:10.1002/bmm2.12109 · Cited by 11
Non-viral expression of chimeric antigen receptors with multiplex gene editing in primary T cells
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Self-citationApplications of piggyBac Transposons for Genome Manipulation in Stem Cells
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CAR assembly line: Taking CAR T-cell manufacturing to the next level
Wang, J., & Caimi, P. F. (2024) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2024.101595 · Cited by 10
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“55,58 A comprehensive genotoxicity assessment was performed and submitted as part of the BE-101 regulatory filings, with no issues of significance identified.”
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Antibiotic-Free Gene Vectors: A 25-Year Journey to Clinical Trials
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“No correlation between T-cell lymphoma and the use of the PB transposon has been established [147,148].”
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“While recent experience with piggybac transposon-edited CAR-T therapies have led to concerns of the development of CAR T-cell lymphomas, insertional mutagenesis has not been demonstrated in follow-up studies [121,122].”
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Expect the unexpected: piggyBac and lymphoma.
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Malignancies after Chimeric Antigen Receptor T Cell Therapy
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Developing anti-TDE vaccine for sensitizing cancer cells to treatment and metastasis control
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Metadata
- Authors
- Bishop, D. C., Clancy, L. E., Simms, R., Burgess, J., Mathew, G., Moezzi, L., Street, J. A., Sutrave, G., Atkins, E., McGuire, H. M., Gloss, B. S., Lee, K., Jiang, W., Maddock, K., McCaughan, G., Avdic, S., Antonenas, V., O’Brien, T. A., Shaw, P. J., Irving, D. O., Gottlieb, D. J., Blyth, E., & Micklethwaite, K. P.
- Affiliations
- The University of Sydney (AU)
- Westmead Institute for Medical Research (AU)
- Westmead Hospital (AU)
- NSW Health Pathology (AU)
- Children’s Cancer Institute, Sydney, NSW, Australia;
- University of Technology Sydney (AU)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2021-10-21
- Volume
- 138
- Issue
- 16
- Pages
- 1504-1509
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W3160982226
- Cited by
- 177
- References
- 27
- Citations by year
- 2026: 20 · 2025: 35 · 2024: 45 · 2023: 31 · 2022: 29 · 2021: 17
- FWCI
- 11.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- David and Elaine Potter Foundation
- Ian Potter Foundation
- Cancer Australia (1047454)
- Cancer Institute NSW
- Cure Cancer Australia Foundation
- Medical Research Council
- National Health and Medical Research Council (1102172)
- Cancer Council NSW
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CAR T-cell therapy, piggyBac transposon, CD19, T-cell leukemia, B-cell acute lymphoblastic leukemia
- MeSH terms
- Adult, Aged, DNA Transposable Elements, Female, Humans, Lymphoma, Male, Middle Aged, Receptors, Antigen, T-Cell, Leukemia, B-Cell, Immunotherapy, Adoptive, Lymphoma, B-Cell, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Young Adult
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