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Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma.

ABSTRACT: Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated with treatment delays due to the required logistics. We hypothesized that point of care manufacturing of CAR-T cells on the automated CliniMACS Prodigy® device allows reproducible and fast delivery of cells for the treatment of patients with non-Hodgkin lymphoma. Here we describe cell manufacturing results and characterize the phenotype and effector function of CAR-T cells used in a phase I/II study. We utilized a lentiviral vector delivering a second-generation CD19 CAR construct with 4-1BB costimulatory domain and TNFRSF19 transmembrane domain. Our data highlight the successful generation of CAR-T cells at numbers sufficient for all patients treated, a shortened duration of production from 12 to 8 days followed by fresh infusion into patients, and the detection of CAR-T cells in patient circulation up to 1-year post-infusion.

SUBMITTER: Jackson Z

PROVIDER: S-EPMC7427107 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma.

Jackson Zachary Z Roe Anne A Sharma Ashish Arunkumar AA Lopes Filipa Blasco Tavares Pereira FBTP Talla Aarthi A Kleinsorge-Block Sarah S Zamborsky Kayla K Schiavone Jennifer J Manjappa Shivaprasad S Schauner Robert R Lee Grace G Liu Ruifu R Caimi Paolo F PF Xiong Ying Y Krueger Winfried W Worden Andrew A Kadan Mike M Schneider Dina D Orentas Rimas R Dropulic Boro B Sekaly Rafick-Pierre RP de Lima Marcos M Wald David N DN Reese Jane S JS

Frontiers in immunology 20200807

Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated with treatment delays due to the required logistics. We hypothesized that point of care manufacturing of CAR-T cells on the automated CliniMACS Prodigy<sup>®</sup> device allows reproducible and fast delivery of cells for the treatment of patients w ...[more]

PMID: 32849651

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Project description:BackgroundThe use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL.MethodsWe performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed.ResultsFrom August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (Cmax) values than other patients. Responders had higher Cmax and area under the curve values than non-responders. Tumour burden and Cmax were potentially associated with the severity of CRS.ConclusionsThis study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy.Clinical trial registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Dataset Information

Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma.

Publications

Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma.

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