Phase i trials using sleeping beauty to generate CD19-specific CAR T cells

Partow Kebriaei; Harjeet Singh; M. Helen Huls; Matthew J. Figliola; Roland Bassett; Simon Olivares; Bipulendu Jena; Margaret J. Dawson; Pappanaicken R. Kumaresan; Shihuang Su; Sourindra Maiti; Jianliang Dai; Branden Moriarity; Marie Andrée Forget; Vladimir Senyukov; Aaron Orozco; Tingting Liu; Jessica McCarty; Rineka N. Jackson; Judy S. Moyes; Gabriela Rondon; Muzaffar Qazilbash; Stefan Ciurea; Amin Alousi; Yago Nieto; Katy Rezvani; David Marin; Uday Popat; Chitra Hosing; Elizabeth J. Shpall; Hagop Kantarjian; Michael Keating; William Wierda; Kim Anh Do; David A. Largaespada; Dean A. Lee; Perry B. Hackett; Richard E. Champlin; Laurence J N Cooper

doi:10.1172/JCI86721

Phase i trials using sleeping beauty to generate CD19-specific CAR T cells

Partow Kebriaei, Harjeet Singh, M. Helen Huls, Matthew J. Figliola, Roland Bassett, Simon Olivares, Bipulendu Jena, Margaret J. Dawson, Pappanaicken R. Kumaresan, Shihuang Su, Sourindra Maiti, Jianliang Dai, Branden Moriarity, Marie Andrée Forget, Vladimir Senyukov, Aaron Orozco, Tingting Liu, Jessica McCarty, Rineka N. Jackson, Judy S. MoyesGabriela Rondon, Muzaffar Qazilbash, Stefan Ciurea, Amin Alousi, Yago Nieto, Katy Rezvani, David Marin, Uday Popat, Chitra Hosing, Elizabeth J. Shpall, Hagop Kantarjian, Michael Keating, William Wierda, Kim Anh Do, David A. Largaespada, Dean A. Lee, Perry B. Hackett, Richard E. Champlin, Laurence J N Cooper

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Abstract

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.

Original language	English (US)
Pages (from-to)	3363-3376
Number of pages	14
Journal	Journal of Clinical Investigation
Volume	126
Issue number	9
DOIs	https://doi.org/10.1172/JCI86721
State	Published - Sep 1 2016

Bibliographical note

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

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Kebriaei, P., Singh, H., Huls, M. H., Figliola, M. J., Bassett, R., Olivares, S., Jena, B., Dawson, M. J., Kumaresan, P. R., Su, S., Maiti, S., Dai, J., Moriarity, B., Forget, M. A., Senyukov, V., Orozco, A., Liu, T., McCarty, J., Jackson, R. N., ... Cooper, L. J. N. (2016). Phase i trials using sleeping beauty to generate CD19-specific CAR T cells. Journal of Clinical Investigation, 126(9), 3363-3376. https://doi.org/10.1172/JCI86721

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, LJN 2016, 'Phase i trials using sleeping beauty to generate CD19-specific CAR T cells', Journal of Clinical Investigation, vol. 126, no. 9, pp. 3363-3376. https://doi.org/10.1172/JCI86721

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title = "Phase i trials using sleeping beauty to generate CD19-specific CAR T cells",

abstract = "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.",

author = "Partow Kebriaei and Harjeet Singh and Huls, {M. Helen} and Figliola, {Matthew J.} and Roland Bassett and Simon Olivares and Bipulendu Jena and Dawson, {Margaret J.} and Kumaresan, {Pappanaicken R.} and Shihuang Su and Sourindra Maiti and Jianliang Dai and Branden Moriarity and Forget, {Marie Andr{\'e}e} and Vladimir Senyukov and Aaron Orozco and Tingting Liu and Jessica McCarty and Jackson, {Rineka N.} and Moyes, {Judy S.} and Gabriela Rondon and Muzaffar Qazilbash and Stefan Ciurea and Amin Alousi and Yago Nieto and Katy Rezvani and David Marin and Uday Popat and Chitra Hosing and Shpall, {Elizabeth J.} and Hagop Kantarjian and Michael Keating and William Wierda and Do, {Kim Anh} and Largaespada, {David A.} and Lee, {Dean A.} and Hackett, {Perry B.} and Champlin, {Richard E.} and Cooper, {Laurence J N}",

note = "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",

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doi = "10.1172/JCI86721",

language = "English (US)",

volume = "126",

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journal = "Journal of Clinical Investigation",

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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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ER -

Phase i trials using sleeping beauty to generate CD19-specific CAR T cells

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