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image of Secondary Malignancies of Chimeric Antigen Receptor T-cell Therapy: A Multidimensional Analysis of Mechanisms, Risk Factors, and Treatment Strategies

Abstract

Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a pioneering advancement in immunotherapy, demonstrating substantial clinical success in the treatment of hematologic malignancies, particularly in B-cell hematologic malignancies. This therapeutic approach involves the genetic modification of a patient's T-cells to express receptors specific to tumor antigens, thereby enabling the CAR T-cells to identify and eradicate tumor cells, which significantly enhances the patient's treatment prognosis. Despite the remarkable efficacy of CAR-T therapy, concerns regarding its safety have emerged during clinical implementation. Notably, research has indicated that CAR T-cell therapy may be associated with the development of secondary primary malignancies, prompting considerable apprehension within the clinical community regarding the long-term adverse effects of this treatment modality. This article aims to investigate the potential mechanisms responsible for the induction of secondary primary malignancies by CAR T-cells, evaluate the associated risk factors, and discuss therapeutic strategies to mitigate this issue. Furthermore, the article will explore future research directions focused on optimizing the safety profile of CAR-T therapy, thereby providing a theoretical foundation for the development of safer and more effective therapeutic interventions.

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2025-06-26
2025-09-27

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References

  1. Li Y.R. Lyu Z. Chen Y. Fang Y. Yang L. Frontiers in CAR-T cell therapy for autoimmune diseases. Trends Pharmacol. Sci. 2024 45 9 839 857 10.1016/j.tips.2024.07.005 39147651
    [Google Scholar]
  2. Haradhvala N.J. Leick M.B. Maurer K. Gohil S.H. Larson R.C. Yao N. Gallagher K.M.E. Katsis K. Frigault M.J. Southard J. Li S. Kann M.C. Silva H. Jan M. Rhrissorrakrai K. Utro F. Levovitz C. Jacobs R.A. Slowik K. Danysh B.P. Livak K.J. Parida L. Ferry J. Jacobson C. Wu C.J. Getz G. Maus M.V. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat. Med. 2022 28 9 1848 1859 10.1038/s41591‑022‑01959‑0 36097221
    [Google Scholar]
  3. Cappell K.M. Kochenderfer J.N. Long-term outcomes following CAR T cell therapy: What we know so far. Nat. Rev. Clin. Oncol. 2023 20 6 359 371 10.1038/s41571‑023‑00754‑1 37055515
    [Google Scholar]
  4. Hamilton M.P. Sugio T. Noordenbos T. Shi S. Bulterys P.L. Liu C.L. Kang X. Olsen M.N. Good Z. Dahiya S. Frank M.J. Sahaf B. Mackall C.L. Gratzinger D. Diehn M. Alizadeh A.A. Miklos D.B. Risk of second tumors and T-Cell lymphoma after CAR T-cell therapy. N. Engl. J. Med. 2024 390 22 2047 2060 10.1056/NEJMoa2401361 38865660
    [Google Scholar]
  5. Patel S.A. Spiegel J.Y. Dahiya S. Second primary cancer after chimeric antigen receptor-T-cell therapy: A review. JAMA Oncol. 2025 11 2 174 181 10.1001/jamaoncol.2024.5412 39666320
    [Google Scholar]
  6. Tix T. Alhomoud M. Shouval R. Cliff E.R.S. Perales M.A. Cordas dos Santos D.M. Rejeski K. Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients. Clin. Cancer Res. 2024 30 20 4690 4700 10.1158/1078‑0432.CCR‑24‑1798 39256908
    [Google Scholar]
  7. Henderson T.O. Liu Q. Turcotte L.M. Neglia J.P. Leisenring W. Hodgson D. Diller L. Kenney L. Morton L. Berrington de Gonzalez A. Arnold M. Bhatia S. Howell R.M. Smith S.A. Robison L.L. Armstrong G.T. Oeffinger K.C. Yasui Y. Moskowitz C.S. Association of changes in cancer therapy over 3 decades with risk of subsequent breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS). JAMA Oncol. 2022 8 12 1765 1774 10.1001/jamaoncol.2022.4649 36227603
    [Google Scholar]
  8. Ghilardi G. Fraietta J.A. Gerson J.N. Van Deerlin V.M. Morrissette J.J.D. Caponetti G.C. Paruzzo L. Harris J.C. Chong E.A. Susanibar Adaniya S.P. Svoboda J. Nasta S.D. Ugwuanyi O.H. Landsburg D.J. Fardella E. Waxman A.J. Chong E.R. Patel V. Pajarillo R. Kulikovskaya I. Lieberman D.B. Cohen A.D. Levine B.L. Stadtmauer E.A. Frey N.V. Vogl D.T. Hexner E.O. Barta S.K. Porter D.L. Garfall A.L. Schuster S.J. June C.H. Ruella M. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat. Med. 2024 30 4 984 989 10.1038/s41591‑024‑02826‑w 38266761
    [Google Scholar]
  9. Cordeiro A. Bezerra E.D. Hirayama A.V. Hill J.A. Wu Q.V. Voutsinas J. Sorror M.L. Turtle C.J. Maloney D.G. Bar M. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biol. Blood Marrow Transplant. 2020 26 1 26 33 10.1016/j.bbmt.2019.08.003 31419568
    [Google Scholar]
  10. Pasquini M.C. Hu Z.H. Curran K. Laetsch T. Locke F. Rouce R. Pulsipher M.A. Phillips C.L. Keating A. Frigault M.J. Salzberg D. Jaglowski S. Sasine J.P. Rosenthal J. Ghosh M. Landsburg D. Margossian S. Martin P.L. Kamdar M.K. Hematti P. Nikiforow S. Turtle C. Perales M.A. Steinert P. Horowitz M.M. Moskop A. Pacaud L. Yi L. Chawla R. Bleickardt E. Grupp S. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020 4 21 5414 5424 10.1182/bloodadvances.2020003092 33147337
    [Google Scholar]
  11. Jacobson C.A. Locke F.L. Ma L. Asubonteng J. Hu Z.H. Siddiqi T. Ahmed S. Ghobadi A. Miklos D.B. Lin Y. Perales M.A. Lunning M.A. Herr M.M. Hill B.T. Ganguly S. Dong H. Nikiforow S. Hooper M. Kawashima J. Xu H. Pasquini M.C. Real-world evidence of axicabtagene ciloleucel for the treatment of large B Cell lymphoma in the United States. Transplant. Cell. Ther. 2022 28 9 581.e1 581.e8 10.1016/j.jtct.2022.05.026 35609867
    [Google Scholar]
  12. Paolo Strati Ankur Varma; Sherry Adkins; Jason Westin; Felipe Samaniego; Sairah Ahmed; Yiming Chen; Sandra Horowitz; Sara Arafat; Swapna Johncy; Partow Kebriaei; Chen, Y.; Horowitz, S.; Arafat, S.; Johncy, S.; Kebriaei, P.; Mulanovich, V.E.; Ariza Heredia, E.; Neelapu, S.S. Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma. Haematologica 2020 106 10 2667 2672 10.3324/haematol.2020.254045 32732355
    [Google Scholar]
  13. Alkhateeb H.B. Mohty R. Greipp P. Bansal R. Hathcock M. Rosenthal A. Murthy H. Kharfan-Dabaja M. Bisneto Villasboas J.C. Bennani N. Ansell S.M. Patnaik M.M. Litzow M.R. He R. Chen D. Al-Kali A. Kenderian S.S. Lin Y. Shah M.V. Therapy-related myeloid neoplasms following chimeric antigen receptor T-cell therapy for Non-Hodgkin Lymphoma. Blood Cancer J. 2022 12 7 113 10.1038/s41408‑022‑00707‑4 35882844
    [Google Scholar]
  14. Gurney M. Baranwal A. Rosenthal A. Kharfan-Dabaja M.A. Kenderian S.S. Lin Y. Shah M.V. Features and factors associated with myeloid neoplasms after chimeric antigen receptor T-cell therapy. JAMA Oncol. 2024 10 4 532 535 10.1001/jamaoncol.2023.7182 38386311
    [Google Scholar]
  15. Elsallab M. Ellithi M. Lunning M.A. D’Angelo C. Ma J. Perales M.A. Frigault M. Maus M.V. Second primary malignancies after commercial CAR T-cell therapy: Analysis of the FDA Adverse Events Reporting System. Blood 2024 143 20 2099 2105 10.1182/blood.2024024166 38483155
    [Google Scholar]
  16. Berdeja J.G. Madduri D. Usmani S.Z. Jakubowiak A. Agha M. Cohen A.D. Stewart A.K. Hari P. Htut M. Lesokhin A. Deol A. Munshi N.C. O’Donnell E. Avigan D. Singh I. Zudaire E. Yeh T.M. Allred A.J. Olyslager Y. Banerjee A. Jackson C.C. Goldberg J.D. Schecter J.M. Deraedt W. Zhuang S.H. Infante J. Geng D. Wu X. Carrasco-Alfonso M.J. Akram M. Hossain F. Rizvi S. Fan F. Lin Y. Martin T. Jagannath S. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet 2021 398 10297 314 324 10.1016/S0140‑6736(21)00933‑8 34175021
    [Google Scholar]
  17. Barone A. Chiappella A. Casadei B. Bramanti S. Ljevar S. Chiusolo P. Di Rocco A. Tisi M.C. Barbui A.M. Farina M. Brunello L. Di Chio M.C. Novo M. Musso M. Olivieri J. Trotta G.E. Dodero A. Aiello A. Corradini P. Secondary primary malignancies after CD‐19 directed CAR ‐T‐cell therapy in lymphomas: A report from the Italian CART ‐ SIE study. Br. J. Haematol. 2024 205 4 1356 1360 10.1111/bjh.19590 38877876
    [Google Scholar]
  18. Falini L. Venanzi A. Tini V. Innocente A. Ballanti S. Saldi S. Sivolella S. Pierini A. Aristei C. Tiacci E. Perriello V.M. Falini B. Acute myeloid leukemia development soon after anti-CD19 chimeric antigen receptor T-cell infusion in a patient with refractory diffuse large B-cell lymphoma and pre-existing clonal hematopoiesis. Haematologica 2022 108 1 290 294 10.3324/haematol.2022.281351 35899391
    [Google Scholar]
  19. Zhao A. Zhao M. Qian W. Liang A. Li P. Liu H. Secondary myeloid neoplasms after CD19 CAR T therapy in patients with refractory/relapsed B-cell lymphoma: Case series and review of literature. Front. Immunol. 2023 13 1063986 10.3389/fimmu.2022.1063986 36713414
    [Google Scholar]
  20. Volery F. Banz Y. Heini A. Kronig M.N. Siegrist D. Daskalakis M. Bacher U. Pabst T. Therapy-related acute myeloid leukemia after CAR-T cell therapy with brexucabtagene autoleucel for mantle cell lymphoma. Case Rep. Oncol. 2024 17 1 1087 1093 10.1159/000541256 39474550
    [Google Scholar]
  21. Lorenc R. Shouval R. Flynn J.R. Devlin S.M. Saldia A. De Abia A.L. De Lapuerta M.C. Tomas A.A. Cassanello G. Leslie L.A. Rejeski K. Lin R.J. Scordo M. Shah G.L. Palomba M.L. Salles G. Park J. Giralt S.A. Perales M.A. Ip A. Dahi P.B. Subsequent malignancies after CD19-targeted chimeric antigen receptor T cells in patients with lymphoma. Transplant. Cell. Ther. 2024 30 10 990 1000 10.1016/j.jtct.2024.06.027 38972512
    [Google Scholar]
  22. Verdun N. Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 2024 390 7 584 586 10.1056/NEJMp2400209 38265704
    [Google Scholar]
  23. Bangolo A. Amoozgar B. Zhang L. Nagesh V.K. Sekhon I. Weissman S. Vesole D. Phull P. Donato M. Biran N. Siegel D. Parmar H. Impact of allogeneic stem cell transplant on safety and outcomes of chimeric antigen receptor T cell (CAR-T) therapy in patients with multiple myeloma (MM). J. Clin. Med. 2024 13 20 6207 10.3390/jcm13206207 39458157
    [Google Scholar]
  24. Bouziana S. Bouzianas D. The current landscape of secondary malignancies after CAR T-cell therapies: How could malignancies be prevented? Int. J. Mol. Sci. 2024 25 17 9518 10.3390/ijms25179518 39273462
    [Google Scholar]
  25. Zhou Z. Zhang G. Xu Y. Yang S. Wang J. Li Z. Peng F. Lu Q. The underlying mechanism of chimeric antigen receptor (CAR)-T cell therapy triggering secondary T-cell cancers: Mystery of the Sphinx? Cancer Lett. 2024 597 217083 10.1016/j.canlet.2024.217083 38925363
    [Google Scholar]
  26. Shao L. Shi R. Zhao Y. Liu H. Lu A. Ma J. Cai Y. Fuksenko T. Pelayo A. Shah N.N. Kochenderfer J.N. Norberg S.M. Hinrichs C. Highfill S.L. Somerville R.P. Panch S.R. Jin P. Stroncek D.F. Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products. J. Transl. Med. 2022 20 1 514 10.1186/s12967‑022‑03729‑5 36348415
    [Google Scholar]
  27. Abou-el-Enein M. The fate(s) of CAR T-Cell therapy: Navigating the risks of CAR+ T-Cell malignancy. Blood Cancer Discov. 2024 5 4 249 257 10.1158/2643‑3230.BCD‑23‑0272 38713831
    [Google Scholar]
  28. Suleman S. Khalifa M.S. Fawaz S. Alhaque S. Chinea Y. Themis M. Analysis of hiv-1-based lentiviral vector particle composition by pacbio long-read nucleic acid sequencing. Hum. Gene Ther. 2025 36 5-6 628 636 10.1089/hum.2024.121 39973307
    [Google Scholar]
  29. Cornetta K. Koop S. Nance E. House K. Duffy L. Replication-competent lentivirus analysis of vector-transduced T cell products used in cancer immunotherapy clinical trials. Methods Mol. Biol. 2020 2086 181 194 10.1007/978‑1‑0716‑0146‑4_13 31707676
    [Google Scholar]
  30. Park J. Daniels J. Wartewig T. Ringbloom K.G. Martinez-Escala M.E. Choi S. Thomas J.J. Doukas P.G. Yang J. Snowden C. Law C. Lee Y. Lee K. Zhang Y. Conran C. Tegtmeyer K. Mo S.H. Pease D.R. Jothishankar B. Kwok P.Y. Abdulla F.R. Pro B. Louissaint A. Boggon T.J. Sosman J. Guitart J. Rao D. Ruland J. Choi J. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. Blood 2021 138 14 1225 1236 10.1182/blood.2020009655 34115827
    [Google Scholar]
  31. Daniels J. Choi J. BACH2 is a putative T-cell lymphoma tumor suppressor that may play a role in product-derived CAR T-cell lymphomas. Blood 2021 138 25 2731 2733 10.1182/blood.2021012641 34499707
    [Google Scholar]
  32. Moretti A. Ponzo M. Nicolette C.A. Tcherepanova I.Y. Biondi A. Magnani C.F. The past, present, and future of non-viral CAR T cells. Front. Immunol. 2022 13 867013 10.3389/fimmu.2022.867013 35757746
    [Google Scholar]
  33. Hsieh E.M. Myers R.M. Yates B. Annesley C. John S. Taraseviciute A. Steinberg S.M. Sheppard J. Chung P. Chen L. Lee D.W. DiNofia A. Grupp S.A. Verneris M.R. Laetsch T.W. Bhojwani D. Brown P.A. Pulsipher M.A. Rheingold S.R. Gardner R.A. Gore L. Shah N.N. Lamble A.J. Low rate of subsequent malignant neoplasms after CD19 CAR T-cell therapy. Blood Adv. 2022 6 17 5222 5226 10.1182/bloodadvances.2022008093 35834728
    [Google Scholar]
  34. Mustafa A.H.M. Krämer O.H. Pharmacological modulation of the crosstalk between aberrant janus kinase signaling and epigenetic modifiers of the histone deacetylase family to treat cancer. Pharmacol. Rev. 2023 75 1 35 61 10.1124/pharmrev.122.000612 36752816
    [Google Scholar]
  35. Parreno V. Loubiere V. Schuettengruber B. Fritsch L. Rawal C.C. Erokhin M. Győrffy B. Normanno D. Di Stefano M. Moreaux J. Butova N.L. Chiolo I. Chetverina D. Martinez A.M. Cavalli G. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature 2024 629 8012 688 696 10.1038/s41586‑024‑07328‑w 38658752
    [Google Scholar]
  36. Braun T. Rade M. Merz M. Klepzig H. Große F. Fandrei D. Pham N.N. Kreuz M. Kuhn C.K. Kuschel F. Löffler D. Meinel J. Heger E. Schweinsberg V. Pflug N. Platzbecker U. Hallek M. Holtick U. Köhl U. Scheid C. Reiche K. Herling M. Richardson T. Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody. Nat. Med. 2025 31 4 1145 1153 10.1038/s41591‑025‑03499‑9 39984633
    [Google Scholar]
  37. Yeung C.C.S. Woolston D.W. Nguyen T. Lee K. Naresh K. Fang M. Exploring the pathogenetic implications of post CAR-T/TCR-T infusion clonal cytogenetic abnormalities. Transplant. Cell. Ther. 2025 31 2 S12 10.1016/j.jtct.2025.01.022
    [Google Scholar]
  38. Chihara D. Dores G.M. Flowers C.R. Morton L.M. The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma. Blood 2021 138 9 785 789 10.1182/blood.2020010497 33822002
    [Google Scholar]
  39. Yi D. Gergis M. Hsu J. Yang Y. Bi X. Aljurf M. Gergis U. Next-generation chimeric antigen receptor T-cells. Hematol. Oncol. Stem Cell Ther. 2022 15 3 117 121 10.56875/2589‑0646.1035 36537905
    [Google Scholar]
  40. Shimabukuro-Vornhagen A. Gödel P. Subklewe M. Stemmler H.J. Schlößer H.A. Schlaak M. Kochanek M. Böll B. von Bergwelt-Baildon M.S. Cytokine release syndrome. J. Immunother. Cancer 2018 6 1 56 10.1186/s40425‑018‑0343‑9 29907163
    [Google Scholar]
  41. Virlan A.T. Cafaro G. Sunzini F. Degboe Y. Christodoulou M.I. Immune-checkpoint inhibitors in anti-cancer armamentarium: A double-edged sword in risk of developing autoimmunity and immune-related adverse effects. Front. Oncol. 2024 14 14 1476475 10.3389/fonc.2024.1476475 39252949
    [Google Scholar]
  42. Ruella M. Korell F. Porazzi P. Maus M.V. Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies. Nat. Rev. Drug Discov. 2023 22 12 976 995 10.1038/s41573‑023‑00807‑1 37907724
    [Google Scholar]
  43. de Visser K.E. Joyce J.A. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023 41 3 374 403 10.1016/j.ccell.2023.02.016 36917948
    [Google Scholar]
  44. Wang K. Coutifaris P. Brocks D. Wang G. Azar T. Solis S. Nandi A. Anderson S. Han N. Manne S. Kiner E. Sachar C. Lucas M. George S. Yan P.K. Kier M.W. Laughlin A.I. Kothari S. Giles J. Mathew D. Ghinnagow R. Alanio C. Flowers A. Xu W. Tenney D.J. Xu X. Amaravadi R.K. Karakousis G.C. Schuchter L.M. Buggert M. Oldridge D. Minn A.J. Blank C. Weber J.S. Mitchell T.C. Farwell M.D. Herati R.S. Huang A.C. Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells. Cancer Cell 2024 42 9 1582 1597.e10 10.1016/j.ccell.2024.08.007 39214097
    [Google Scholar]
  45. Levine J.E. Grupp S.A. Pulsipher M.A. Dietz A.C. Rives S. Myers G.D. August K.J. Verneris M.R. Buechner J. Laetsch T.W. Bittencourt H. Baruchel A. Boyer M.W. De Moerloose B. Qayed M. Davies S.M. Phillips C.L. Driscoll T.A. Bader P. Schlis K. Wood P.A. Mody R. Yi L. Leung M. Eldjerou L.K. June C.H. Maude S.L. Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J. Immunother. Cancer 2021 9 8 e002287 10.1136/jitc‑2020‑002287 34353848
    [Google Scholar]
  46. Cappell K.M. Sherry R.M. Yang J.C. Goff S.L. Vanasse D.A. McIntyre L. Rosenberg S.A. Kochenderfer J.N. Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J. Clin. Oncol. 2020 38 32 3805 3815 10.1200/JCO.20.01467 33021872
    [Google Scholar]
  47. Shen J. Hu R. Lin A. Jiang A. Tang B. Liu Z. Cheng Q. Miao K. Zhang J. Luo P. Characterization of second primary malignancies post CAR T-cell therapy: real-world insights from the two global pharmacovigilance databases of FAERS and VigiBase. EClinicalMedicine 2024 73 102684 10.1016/j.eclinm.2024.102684 39007060
    [Google Scholar]
  48. Wang A.X. Ong X.J. D’Souza C. Neeson P.J. Zhu J.J. Combining chemotherapy with CAR-T cell therapy in treating solid tumors. Front. Immunol. 2023 14 1140541 10.3389/fimmu.2023.1140541 36949946
    [Google Scholar]
  49. Amini L. Silbert S.K. Maude S.L. Nastoupil L.J. Ramos C.A. Brentjens R.J. Sauter C.S. Shah N.N. Abou-el-Enein M. Preparing for CAR T cell therapy: Patient selection, bridging therapies and lymphodepletion. Nat. Rev. Clin. Oncol. 2022 19 5 342 355 10.1038/s41571‑022‑00607‑3 35318469
    [Google Scholar]
  50. Lutfi F. Holtzman N.G. Kansagra A.J. Mustafa Ali M. Bukhari A. Yan J. Samanta S. Gottlieb D. Kim D.W. Matsumoto L.R. Gahres N. Ruehle K. Hankey K.G. Douglas T. Lee S.T. Law J.Y. Kocoglu M.H. Atanackovic D. Yared J.A. Hardy N.M. Molitoris J. Mohindra P. Rapoport A.P. Dahiya S. The impact of bridging therapy prior to CD19‐directed chimeric antigen receptor T‐cell therapy in patients with large B‐cell lymphoma. Br. J. Haematol. 2021 195 3 405 412 10.1111/bjh.17738 34500492
    [Google Scholar]
  51. Fabrizio V.A. Boelens J.J. Mauguen A. Baggott C. Prabhu S. Egeler E. Mavroukakis S. Pacenta H. Phillips C.L. Rossoff J. Stefanski H.E. Talano J.A. Moskop A. Margossian S.P. Verneris M.R. Myers G.D. Karras N.A. Brown P.A. Qayed M. Hermiston M. Satwani P. Krupski C. Keating A.K. Wilcox R. Rabik C.A. Chinnabhandar V. Kunicki M. Goksenin A.Y. Mackall C.L. Laetsch T.W. Schultz L.M. Curran K.J. Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv. 2022 6 7 1961 1968 10.1182/bloodadvances.2021006418 34788386
    [Google Scholar]
  52. Durando M. Gopal A.K. Tuscano J. Persky D. A systematic review of clinical applications of anti-CD20 radioimmunotherapy for lymphoma. Oncologist 2024 29 4 278 288 10.1093/oncolo/oyad333 38207010
    [Google Scholar]
  53. Al-Juhaishi T. Khurana A. Shafer D. Therapy-related myeloid neoplasms in lymphoma survivors: Reducing risks. Best Pract. Res. Clin. Haematol. 2019 32 1 47 53 10.1016/j.beha.2019.02.008 30927975
    [Google Scholar]
  54. Levine B.L. Pasquini M.C. Connolly J.E. Porter D.L. Gustafson M.P. Boelens J.J. Horwitz E.M. Grupp S.A. Maus M.V. Locke F.L. Ciceri F. Ruggeri A. Snowden J. Heslop H.E. Mackall C.L. June C.H. Sureda A.M. Perales M.A. Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nat. Med. 2024 30 2 338 341 10.1038/s41591‑023‑02767‑w 38195751
    [Google Scholar]
  55. Kwon M. Iacoboni G. Reguera J.L. Corral L.L. Morales R.H. Ortiz-Maldonado V. Guerreiro M. Caballero A.C. Domínguez M.L.G. Pina J.M.S. Mussetti A. Sancho J.M. Bastos-Oreiro M. Catala E. Delgado J. Henriquez H.L. Sanz J. Calbacho M. Bailén R. Carpio C. Ribera J.M. Sureda A. Briones J. Hernandez-Boluda J.C. Cebrián N.M. Martin J.L.D. Martín A. Barba P. Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma. Haematologica 2022 108 1 110 121 10.3324/haematol.2022.280805 35770532
    [Google Scholar]
  56. Neelapu S.S. Jacobson C.A. Ghobadi A. Miklos D.B. Lekakis L.J. Oluwole O.O. Lin Y. Braunschweig I. Hill B.T. Timmerman J.M. Deol A. Reagan P.M. Stiff P. Flinn I.W. Farooq U. Goy A.H. McSweeney P.A. Munoz J. Siddiqi T. Chavez J.C. Herrera A.F. Bartlett N.L. Bot A.A. Shen R.R. Dong J. Singh K. Miao H. Kim J.J. Zheng Y. Locke F.L. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood 2023 141 19 2307 2315 36821768
    [Google Scholar]
  57. Westin J.R. Oluwole O.O. Kersten M.J. Miklos D.B. Perales M.A. Ghobadi A. Rapoport A.P. Sureda A. Jacobson C.A. Farooq U. van Meerten T. Ulrickson M. Elsawy M. Leslie L.A. Chaganti S. Dickinson M. Dorritie K. Reagan P.M. McGuirk J. Song K.W. Riedell P.A. Minnema M.C. Yang Y. Vardhanabhuti S. Filosto S. Cheng P. Shahani S.A. Schupp M. To C. Locke F.L. ZUMA-7 Investigators: Kite members. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N. Engl. J. Med. 2023 389 2 148 157 10.1056/NEJMoa2301665 37272527
    [Google Scholar]
  58. Abramson J.S. Palomba M.L. Gordon L.I. Lunning M. Wang M. Arnason J. Purev E. Maloney D.G. Andreadis C. Sehgal A. Solomon S.R. Ghosh N. Dehner C. Kim Y. Ogasawara K. Kostic A. Siddiqi T. Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood 2024 143 5 404 416 10.1182/blood.2023020854 37890149
    [Google Scholar]
  59. Abramson J.S. Solomon S.R. Arnason J. Johnston P.B. Glass B. Bachanova V. Ibrahimi S. Mielke S. Mutsaers P. Hernandez-Ilizaliturri F. Izutsu K. Morschhauser F. Lunning M. Crotta A. Montheard S. Previtali A. Ogasawara K. Kamdar M. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: Primary analysis of the phase 3 TRANSFORM study. Blood 2023 141 14 1675 1684 10.1182/blood.2022018730 36542826
    [Google Scholar]
  60. Shih S.C.M. Bhella S. Review of CAR T-cell therapy in multiple myeloma: A Canadian perspective. Curr. Oncol. 2024 31 7 3949 3967 10.3390/curroncol31070292 39057164
    [Google Scholar]
  61. Ozdemirli M. Loughney T.M. Deniz E. Chahine J.J. Albitar M. Pittaluga S. Sadigh S. Armand P. Uren A. Anderson K.C. Indolent CD4+ CAR T-cell lymphoma after cilta-cel CAR T-cell therapy. N. Engl. J. Med. 2024 390 22 2074 2082 10.1056/NEJMoa2401530 38865661
    [Google Scholar]
  62. Chen Y. Zheng J. Weng Y. Wu Z. Luo X. Qiu Y. Lin Y. Hu J. Wu Y. Myelodysplasia-related gene mutations are associated with favorable prognosis in patients with TP53-mutant acute myeloid leukemia. Ann. Hematol. 2024 103 4 1211 1220 10.1007/s00277‑024‑05679‑y 38409598
    [Google Scholar]
  63. 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. Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac -modified CD19 CAR T cells. Blood 2021 138 16 1504 1509 10.1182/blood.2021010813 34010392
    [Google Scholar]
  64. 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. Louie R.H.Y. Cai C. Foox J. MacKay M. Sedlazeck F.J. Blombery P. Mason C.E. Luciani F. Gottlieb D.J. Blyth E. Investigation of product-derived lymphoma following infusion of piggyBac -modified CD19 chimeric antigen receptor T cells. Blood 2021 138 16 1391 1405 10.1182/blood.2021010858 33974080
    [Google Scholar]
  65. Saleh K. Arbab A. Ghez D. Bigenwald C. Cotteret S. Marzac C. Pasquier F. Pilorge S. Saada V. Vergé V. Ribrag V. Castilla-Llorente C. Myelodysplastic syndrome following chimeric antigen receptor T-cell therapy treated with allogenic stem cell transplantation. Immunotherapy 2023 15 6 401 407 10.2217/imt‑2022‑0205 36950962
    [Google Scholar]
  66. Accorsi Buttini E. Farina M. Lorenzi L. Polverelli N. Radici V. Morello E. Colnaghi F. Almici C. Ferrari E. Bianchetti A. Leoni A. Re F. Bosio K. Bernardi S. Malagola M. Re A. Russo D. High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review. Front. Oncol. 2023 13 1036455 10.3389/fonc.2023.1036455 36741006
    [Google Scholar]
  67. Harrison S.J. Touzeau C. Kint N. Li K. Nguyen T. Mayeur-Rousse C. Rahman M. Le Bris Y. Er J. Eugene-Lamer J. Haynes N.M. Li J. Abbott R.C. Bodet-Milin C. Moreau A. Letouzé E. Lendvai N. Schecter J.M. Deraedt W. Banerjee A. Lengil T. Vogel M. Foulk B. Zhao H. Smirnov D. Slaughter A. Lonardi C. Lee E. Marquez L. Sankari A. Plaks V. Filho J.O.C. Patel N. Geng D. Gastinne T. Kelly H. Tiong I.S. Eveillard M. Chevallier P. Lade S. Moreau P. Grimmond S. Oliaro J. Tessoulin B. Blombery P. CAR+ T-cell lymphoma after cilta-cel therapy for relapsed or refractory myeloma. N. Engl. J. Med. 2025 392 7 677 685 10.1056/NEJMoa2309728 39938094
    [Google Scholar]
  68. Grégoire C. Melenhorst J.J. Navigating CAR-T cell therapy long-term complications. Nat. Can. 2024 5 12 1768 1770 10.1038/s43018‑024‑00867‑1 39690224
    [Google Scholar]
  69. Mulvey A. Trueb L. Coukos G. Arber C. Novel strategies to manage CAR-T cell toxicity. Nat. Rev. Drug Discov. 2025 10.1038/s41573‑024‑01100‑5 39901030
    [Google Scholar]
  70. Park J.H. Nath K. Devlin S.M. Sauter C.S. Palomba M.L. Shah G. Dahi P. Lin R.J. Scordo M. Perales M.A. Shouval R. Tomas A.A. Cathcart E. Mead E. Santomasso B. Holodny A. Brentjens R.J. Riviere I. Sadelain M. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: Phase 2 trial interim results. Nat. Med. 2023 29 7 1710 1717 10.1038/s41591‑023‑02404‑6 37400640
    [Google Scholar]
  71. Santomasso B.D. Gust J. Perna F. How I treat unique and difficult to manage cases of CAR T-cell therapy associated neurotoxicity. Blood 2023 141 20 blood.2022017604 10.1182/blood.2022017604 36877916
    [Google Scholar]
  72. Oluwole O.O. Kenderian S.S. Shiraz P. Karmali R. Reshef R. McCarthy P.L. Ghosh N. Lazaryan A. Filosto S. Poddar S. Mao D. Peng A. Kilcoyne A. Nahas M. Neelapu S.S. ZUMA-19: A phase 1/2 study of axicabtagene ciloleucel plus lenzilumab in patients with relapsed or refractory large b-cell lymphoma. Blood 2022 140 10318 10320.(Suppl. 1) 10.1182/blood‑2022‑167688
    [Google Scholar]
  73. Li X. Gong N. Tian F. Zhang S. Zhang Y. Wang Y. Qing G. Wang Y. Li F. Xu Y. Zhang L. Wang J. Ni Q. Gan Y. Gu C. Jiang H. Huang X. Shi X. Zhang T. Wu Y. Liang X.J. Suppression of cytokine release syndrome during CAR-T-cell therapy via a subcutaneously injected interleukin-6-adsorbing hydrogel. Nat. Biomed. Eng. 2023 7 9 1129 1141 10.1038/s41551‑023‑01084‑4 37696984
    [Google Scholar]
  74. Reardon S. MEGA-CRISPR tool gives a power boost to cancer-fighting cells. Nature 2024 626 8001 940 10.1038/d41586‑024‑00511‑z 38383653
    [Google Scholar]
  75. Tieu V. Sotillo E. Bjelajac J.R. Chen C. Malipatlolla M. Guerrero J.A. Xu P. Quinn P.J. Fisher C. Klysz D. Mackall C.L. Qi L.S. A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells. Cell 2024 187 5 1278 1295.e20 10.1016/j.cell.2024.01.035 38387457
    [Google Scholar]
  76. Nujoom N. Koyakutty M. Biswas L. Rajkumar T. Nair S.V. Emerging Gene-editing nano-therapeutics for Cancer. Heliyon 2024 10 21 e39323 10.1016/j.heliyon.2024.e39323 39524822
    [Google Scholar]
  77. Lei T. Wang Y. Zhang Y. Yang Y. Cao J. Huang J. Chen J. Chen H. Zhang J. Wang L. Xu X. Gale R.P. Wang L. Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy. Leukemia 2024 38 12 2517 2543 10.1038/s41375‑024‑02444‑y 39455854
    [Google Scholar]
  78. Mukalel A.J. Hamilton A.G. Billingsley M.M. Li J. Thatte A.S. Han X. Safford H.C. Padilla M.S. Papp T. Parhiz H. Weissman D. Mitchell M.J. Oxidized mrna lipid nanoparticles for in situ chimeric antigen receptor monocyte engineering. Adv. Funct. Mater. 2024 34 27 2312038 10.1002/adfm.202312038 39628840
    [Google Scholar]
  79. Parayath N.N. Stephan S.B. Koehne A.L. Nelson P.S. Stephan M.T. In vitro transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat. Commun. 2020 11 1 6080 10.1038/s41467‑020‑19486‑2 33247092
    [Google Scholar]
  80. Álvarez-Benedicto E. Tian Z. Chatterjee S. Orlando D. Kim M. Guerrero E.D. Wang X. Siegwart D.J. Spleen SORT LNP generated in situ CAR T cells extend survival in a mouse model of lymphoreplete B cell lymphoma. Angew. Chem. Int. Ed. 2023 62 44 e202310395 10.1002/anie.202310395 37651468
    [Google Scholar]
  81. Bujak J. Kłęk S. Balawejder M. Kociniak A. Wilkus K. Szatanek R. Orzeszko Z. Welanyk J. Torbicz G. Jęckowski M. Kucharczyk T. Wohadlo Ł. Borys M. Stadnik H. Wysocki M. Kayser M. Słomka M.E. Kosmowska A. Horbacka K. Gach T. Markowska B. Kowalczyk T. Karoń J. Karczewski M. Szura M. Sanecka-Duin A. Blum A. Creating an innovative artificial intelligence-based technology (TCRact) for designing and optimizing T cell receptors for use in cancer immunotherapies: Protocol for an observational trial. JMIR Res. Protoc. 2023 12 e45872 10.2196/45872 37440307
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206378956250618182616
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Secondary Malignancies of Chimeric Antigen Receptor T-cell Therapy: A Multidimensional Analysis of Mechanisms, Risk Factors, and Treatment Strategies
Bentham Science Publishers ; https://doi.org/10.2174/0118715206378956250618182616
/content/journals/acamc/10.2174/0118715206378956250618182616
/content/journals/acamc/10.2174/0118715206378956250618182616
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  • Article Type:     Review Article
Keywords: CAR T-cell therapy ; secondary primary malignancies ; T-cell lymphoma ; genetic engineering

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