TY - JOUR
T1 - Phase i trials using sleeping beauty to generate CD19-specific CAR T cells
AU - Kebriaei, Partow
AU - Singh, Harjeet
AU - Huls, M. Helen
AU - Figliola, Matthew J.
AU - Bassett, Roland
AU - Olivares, Simon
AU - Jena, Bipulendu
AU - Dawson, Margaret J.
AU - Kumaresan, Pappanaicken R.
AU - Su, Shihuang
AU - Maiti, Sourindra
AU - Dai, Jianliang
AU - Moriarity, Branden
AU - Forget, Marie Andrée
AU - Senyukov, Vladimir
AU - Orozco, Aaron
AU - Liu, Tingting
AU - McCarty, Jessica
AU - Jackson, Rineka N.
AU - Moyes, Judy S.
AU - Rondon, Gabriela
AU - Qazilbash, Muzaffar
AU - Ciurea, Stefan
AU - Alousi, Amin
AU - Nieto, Yago
AU - Rezvani, Katy
AU - Marin, David
AU - Popat, Uday
AU - Hosing, Chitra
AU - Shpall, Elizabeth J.
AU - Kantarjian, Hagop
AU - Keating, Michael
AU - Wierda, William
AU - Do, Kim Anh
AU - Largaespada, David A.
AU - Lee, Dean A.
AU - Hackett, Perry B.
AU - Champlin, Richard E.
AU - Cooper, Laurence J.N.
N1 - Funding Information:
We thank the flow cytometry and cellular imaging core facilities at MD Anderson. We thank Pulvarthi Rao (Baylor College of Medicine) for karyotyping and George McNamara (MD Anderson) for editing. The Cancer Center Support Grant core-supported facilities used were Characterized Cell Line Core for fingerprinting of cell lines and GMP facility for generation of T cell products. This study was funded by Cancer Center Core Grant (CA16672); RO1 (CA124782, CA120956, CA141303, CA141303); P01 (CA148600); SPORES (CA100632, CA136411, CA00632); Albert J Ward Foundation; Alex's Lemonade Stand Foundation; Burroughs Wellcome Fund; Cancer Prevention and Research Institute of Texas; Charles B. Goddard Foundation of Texas; CLL Global Research Foundation; Energy Transfer Partners; Estate of Noelan L. Bibler; Gillson Longenbaugh Foundation; Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy; Khalifa Bin Zayed Al Nahyan Foundation; Kleberg Foundation; Leukemia and Lymphoma Society; Lymphoma Research Foundation; Miller Foundation; Mr. Herb Simons; Mr. and Mrs. Joe H. Scales; Mr. Thomas Scott; National Foundation for Cancer Research; Pediatric Cancer Research Foundation; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy; University of Texas MD Anderson Cancer Center Sister Institution Network Fund and Moon Shot Fund; William Lawrence and Blanche Hughes Children's Foundation. Publication under the Creative Commons CC-BY license is not required
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI86721
DO - 10.1172/JCI86721
M3 - Article
C2 - 27482888
AN - SCOPUS:84987810063
SN - 0021-9738
VL - 126
SP - 3363
EP - 3376
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -