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

ABSTRACT: 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.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).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.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.Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036.National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.

SUBMITTER: Kebriaei P

PROVIDER: S-EPMC5004935 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Kebriaei Partow P Singh Harjeet H Huls M Helen MH Figliola Matthew J MJ Bassett Roland R Olivares Simon S Jena Bipulendu B Dawson Margaret J MJ Kumaresan Pappanaicken R PR Su Shihuang S Maiti Sourindra S Dai Jianliang J Moriarity Branden B Forget Marie-Andrée MA Senyukov Vladimir V Orozco Aaron A Liu Tingting T McCarty Jessica J Jackson Rineka N RN Moyes Judy S JS Rondon Gabriela G Qazilbash Muzaffar M Ciurea Stefan S Alousi Amin A Nieto Yago Y Rezvani Katy K Marin David D Popat Uday U Hosing Chitra C Shpall Elizabeth J EJ Kantarjian Hagop H Keating Michael M Wierda William W Do Kim Anh KA Largaespada David A DA Lee Dean A DA Hackett Perry B PB Champlin Richard E RE Cooper Laurence J N LJ

The Journal of clinical investigation 20160802 9

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 27482888

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Project description:BACKGROUNDChimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability.METHODSWe report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells.RESULTSThe cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD-). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion.CONCLUSIONSB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.TRIAL REGISTRATIONClinicalTrials.gov NCT03389035.FUNDINGThis study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).

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

Publications

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

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