دورية أكاديمية
أعرض في EDS

Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells.

التفاصيل البيبلوغرافية
العنوان: Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells.
المؤلفون: Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, Jena B, Dawson MJ, Kumaresan PR, Su S, Maiti S, Dai J, Moriarity B, Forget MA, Senyukov V, Orozco A, Liu T, McCarty J, Jackson RN, Moyes JS, Rondon G, Qazilbash M, Ciurea S, Alousi A, Nieto Y, Rezvani K, Marin D, Popat U, Hosing C, Shpall EJ, Kantarjian H, Keating M, Wierda W, Do KA, Largaespada DA, Lee DA, Hackett PB, Champlin RE, Cooper LJ
المصدر: The Journal of clinical investigation [J Clin Invest] 2016 Sep 01; Vol. 126 (9), pp. 3363-76. Date of Electronic Publication: 2016 Aug 02.
نوع المنشور: Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: DNA Transposable Elements*, Antigens, CD19/*metabolism , Lymphoma, Non-Hodgkin/*therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/*therapy , T-Lymphocytes/*cytology, Adult ; Antigen-Presenting Cells/immunology ; Cytokines/metabolism ; Disease-Free Survival ; Female ; Follow-Up Studies ; Genetic Therapy/methods ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocyte Activation/immunology ; Male ; Middle Aged ; Patient Safety ; Plasmids/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Transplantation, Homologous ; Treatment Outcome ; Young Adult
مستخلص: Background: T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR.
Methods: T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19).
Results: SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients.
Conclusions: CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.
Trial Registration: Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036.
Funding: National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.
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معلومات مُعتمدة: R01 CA141303 United States CA NCI NIH HHS; P30 CA016672 United States CA NCI NIH HHS; R01 CA124782 United States CA NCI NIH HHS; P50 CA100632 United States CA NCI NIH HHS; R01 CA113636 United States CA NCI NIH HHS; P50 CA136411 United States CA NCI NIH HHS; P01 CA148600 United States CA NCI NIH HHS; R01 CA120956 United States CA NCI NIH HHS
سلسلة جزيئية: ClinicalTrials.gov NCT00968760; NCT01497184; NCT01492036
المشرفين على المادة: 0 (Antigens, CD19)
0 (Cytokines)
0 (DNA Transposable Elements)
0 (Receptors, Antigen, T-Cell)
تواريخ الأحداث: Date Created: 20160803 Date Completed: 20170926 Latest Revision: 20220419
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5004935
DOI: 10.1172/JCI86721
PMID: 27482888
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI86721