Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context
Summary: Background: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model. Methods: CASE 2417 was a pha...
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Elsevier
2025-03-01
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| author | Armin Ghobadi Paolo F. Caimi Jane S. Reese Krishna Goparaju Martina di Trani Julie Ritchey Zachary Jackson Benjamin Tomlinson Jennifer M. Schiavone Sarah Kleinsorge-Block Kayla Zamborsky Linda Eissenberg Dina Schneider Kirsten M. Boughan Emily C. Zabor Leland Metheny Molly Gallogly Winfried Kruger Michael Kadan Andrew Worden A.S Ashish Sharma Brenda W. Cooper Folashade Otegbeye Rafick P. Sekaly David N. Wald Carmelo Carlo-Stella John DiPersio Rimas Orentas Boro Dropulic Marcos de Lima |
| author_facet | Armin Ghobadi Paolo F. Caimi Jane S. Reese Krishna Goparaju Martina di Trani Julie Ritchey Zachary Jackson Benjamin Tomlinson Jennifer M. Schiavone Sarah Kleinsorge-Block Kayla Zamborsky Linda Eissenberg Dina Schneider Kirsten M. Boughan Emily C. Zabor Leland Metheny Molly Gallogly Winfried Kruger Michael Kadan Andrew Worden A.S Ashish Sharma Brenda W. Cooper Folashade Otegbeye Rafick P. Sekaly David N. Wald Carmelo Carlo-Stella John DiPersio Rimas Orentas Boro Dropulic Marcos de Lima |
| author_sort | Armin Ghobadi |
| collection | DOAJ |
| description | Summary: Background: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model. Methods: CASE 2417 was a phase I clinical trial. Adults with relapsed or refractory CD19 positive non-Hodgkin lymphoma (R/R NHL) treated with ≥2 prior systemic therapies were eligible. MB-CART-19 is an anti-CD19 CAR T-cell product manufactured using the CliniMACS Prodigy device with 4-1BB and CD3ζ costimulatory domains. Lymphodepletion included fludarabine 25 mg/m2 for 3 days and cyclophosphamide 60 mg/kg for 1 day. Prophylactic tocilizumab was allowed. Three dose levels (0.5, 1.0 and 2.0 × 106 cells/kg) were tested using a 3 + 3 dose-escalation schema. The primary outcome of this study was to determine the safety as defined by the dose limiting toxicities of MB-CART-19 in patients with relapsed and refractory NHL, co-primary outcome was determining the phase 2 dose of MB-CART-19. Secondary outcomes include defining the toxicity profile and to evaluate the initial efficacy of MB-CART-19 against relapsed or refractory NHL. This study was registered in ClinicalTrials.gov NCT03434769. Findings: Thirty-one patients were enrolled between July 2018 and January 2021. Twenty-four (77%) had aggressive lymphoma, 7 (24%) had indolent lymphoma (follicular lymphoma and marginal zone lymphoma). The median number of previous therapies was 5 (range 2–13, interquartile range [IQR] 3–5). All enrolled patients received MB-CART-19. Median apheresis to infusion time was 13 days (range 9–20, IQR 9–13). One dose limiting toxicity (DLT) was observed in dose escalation (fatal cytokine release syndrome [CRS]), whereas one patient died in dose expansion secondary to hemophagocytic syndrome. Both deaths were considered treatment—related. Twenty (65%) patients had CRS, three (10%) grade ≥3. Ten patients (32%) experienced immune effector cell neurotoxicity syndrome (ICANS), four (13%) grade ≥3. Neutropenia (n = 28, 90%), thrombocytopenia (n = 15, 48%) and anaemia (n = 13, 42%) were the most frequent grade ≥3 adverse events. Twenty-five out of 29 (86%, 95% confidence interval [CI]: 68–96%) response-evaluable patients had disease response and 22 (76%, 95% CI: 56–90%) had complete response; the overall and complete response rates for response-evaluable aggressive lymphoma patients (n = 22) were 82% (n = 18, 95% CI: 60–95%) and 73% (n = 16, 95% CI: 50–89%). Median follow up was 24.5 (IQR 17–32) months, median progression free survival (PFS) was 26 months (95% CI: 19-not reached [NR]) and median PFS was not reached (95% CI: 25 months—NR). Two-year estimates of PFS and overall survival (OS) were 63% (95% CI: 47–83%) and 68% (95% CI: 52–88%), respectively. Median PFS was 26 months (95% CI: 7-NR) for aggressive lymphoma patients with 2-year PFS estimate of 53% (95% CI: 36–78%), while median OS had not been reached for aggressive lymphoma patients (95% CI: 19 months-NR), and 2-year OS estimate was 60% (95% CI: 43–85%). Interpretation: Point-of-care CAR T-cell manufacture was feasible and replicable across sites. MB-CART-19 has a safety profile comparable to other CAR T-cell products and high response rates. The recommended phase 2 dose is 2 × 106 MB-CART-19 cells/kg. Short CAR T-cell manufacturing time permits treatment of patients with rapidly progressive lymphoma, a group of patients with high risk disease for whom access to autologous immune effector cellular therapies is usually limited. Funding: This clinical trial was funded through University Hospitals Seidman Cancer Center and Washington University School of Medicine Institutional Funds. Correlative analyses were funded in part by the European Union–Next Generation EU–NRRP M6C2–Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (project #PNRR-MAD-2022-12376059), and the Italian Ministry of Health Ricerca Finalizzata 2019 (project #RF-2019-12370243). |
| format | Article |
| id | doaj-art-857eca7bda0348dba5088ca4a55e7c3d |
| institution | DOAJ |
| issn | 2589-5370 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj-art-857eca7bda0348dba5088ca4a55e7c3d2025-08-20T02:47:21ZengElsevierEClinicalMedicine2589-53702025-03-018110313810.1016/j.eclinm.2025.103138Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in contextArmin Ghobadi0Paolo F. Caimi1Jane S. Reese2Krishna Goparaju3Martina di Trani4Julie Ritchey5Zachary Jackson6Benjamin Tomlinson7Jennifer M. Schiavone8Sarah Kleinsorge-Block9Kayla Zamborsky10Linda Eissenberg11Dina Schneider12Kirsten M. Boughan13Emily C. Zabor14Leland Metheny15Molly Gallogly16Winfried Kruger17Michael Kadan18Andrew Worden A.S19Ashish Sharma20Brenda W. Cooper21Folashade Otegbeye22Rafick P. Sekaly23David N. Wald24Carmelo Carlo-Stella25John DiPersio26Rimas Orentas27Boro Dropulic28Marcos de Lima29Department of Medicine, Washington University School of Medicine, St. Louis, MO, USACase Comprehensive Cancer Center, Cleveland, OH, USA; Department of Haematology and Oncology, Cleveland Clinic, Cleveland, OH, USA; Corresponding author. Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.Case Comprehensive Cancer Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Haematology, IRCCS, Humanitas Research Hospital, Rozzano, Milano, ItalyDepartment of Haematology and Oncology, Cleveland Clinic, Cleveland, OH, USACase Comprehensive Cancer Center, Cleveland, OH, USACase Comprehensive Cancer Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Medicine, Washington University School of Medicine, St. Louis, MO, USALentigen Technology, Inc. a Miltenyi Biotec Company, Gaithersburg, MD, USADepartment of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USADepartment of Haematology and Oncology, Cleveland Clinic, Cleveland, OH, USACase Comprehensive Cancer Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USACase Comprehensive Cancer Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USALentigen Technology, Inc. a Miltenyi Biotec Company, Gaithersburg, MD, USALentigen Technology, Inc. a Miltenyi Biotec Company, Gaithersburg, MD, USALentigen Technology, Inc. a Miltenyi Biotec Company, Gaithersburg, MD, USADepartment of Pathology, Emory University, Atlanta, GA, USACase Comprehensive Cancer Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USAClinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USADepartment of Pathology, Emory University, Atlanta, GA, USACase Comprehensive Cancer Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USADepartment of Haematology, IRCCS, Humanitas Research Hospital, Rozzano, Milano, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milano, ItalyDepartment of Medicine, Washington University School of Medicine, St. Louis, MO, USADepartment of Paediatrics, Seattle Children's Hospital Research Institute, Seattle, WA, USA; Caring Cross, Gaithersburg, MD, USACaring Cross, Gaithersburg, MD, USADepartment of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USASummary: Background: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model. Methods: CASE 2417 was a phase I clinical trial. Adults with relapsed or refractory CD19 positive non-Hodgkin lymphoma (R/R NHL) treated with ≥2 prior systemic therapies were eligible. MB-CART-19 is an anti-CD19 CAR T-cell product manufactured using the CliniMACS Prodigy device with 4-1BB and CD3ζ costimulatory domains. Lymphodepletion included fludarabine 25 mg/m2 for 3 days and cyclophosphamide 60 mg/kg for 1 day. Prophylactic tocilizumab was allowed. Three dose levels (0.5, 1.0 and 2.0 × 106 cells/kg) were tested using a 3 + 3 dose-escalation schema. The primary outcome of this study was to determine the safety as defined by the dose limiting toxicities of MB-CART-19 in patients with relapsed and refractory NHL, co-primary outcome was determining the phase 2 dose of MB-CART-19. Secondary outcomes include defining the toxicity profile and to evaluate the initial efficacy of MB-CART-19 against relapsed or refractory NHL. This study was registered in ClinicalTrials.gov NCT03434769. Findings: Thirty-one patients were enrolled between July 2018 and January 2021. Twenty-four (77%) had aggressive lymphoma, 7 (24%) had indolent lymphoma (follicular lymphoma and marginal zone lymphoma). The median number of previous therapies was 5 (range 2–13, interquartile range [IQR] 3–5). All enrolled patients received MB-CART-19. Median apheresis to infusion time was 13 days (range 9–20, IQR 9–13). One dose limiting toxicity (DLT) was observed in dose escalation (fatal cytokine release syndrome [CRS]), whereas one patient died in dose expansion secondary to hemophagocytic syndrome. Both deaths were considered treatment—related. Twenty (65%) patients had CRS, three (10%) grade ≥3. Ten patients (32%) experienced immune effector cell neurotoxicity syndrome (ICANS), four (13%) grade ≥3. Neutropenia (n = 28, 90%), thrombocytopenia (n = 15, 48%) and anaemia (n = 13, 42%) were the most frequent grade ≥3 adverse events. Twenty-five out of 29 (86%, 95% confidence interval [CI]: 68–96%) response-evaluable patients had disease response and 22 (76%, 95% CI: 56–90%) had complete response; the overall and complete response rates for response-evaluable aggressive lymphoma patients (n = 22) were 82% (n = 18, 95% CI: 60–95%) and 73% (n = 16, 95% CI: 50–89%). Median follow up was 24.5 (IQR 17–32) months, median progression free survival (PFS) was 26 months (95% CI: 19-not reached [NR]) and median PFS was not reached (95% CI: 25 months—NR). Two-year estimates of PFS and overall survival (OS) were 63% (95% CI: 47–83%) and 68% (95% CI: 52–88%), respectively. Median PFS was 26 months (95% CI: 7-NR) for aggressive lymphoma patients with 2-year PFS estimate of 53% (95% CI: 36–78%), while median OS had not been reached for aggressive lymphoma patients (95% CI: 19 months-NR), and 2-year OS estimate was 60% (95% CI: 43–85%). Interpretation: Point-of-care CAR T-cell manufacture was feasible and replicable across sites. MB-CART-19 has a safety profile comparable to other CAR T-cell products and high response rates. The recommended phase 2 dose is 2 × 106 MB-CART-19 cells/kg. Short CAR T-cell manufacturing time permits treatment of patients with rapidly progressive lymphoma, a group of patients with high risk disease for whom access to autologous immune effector cellular therapies is usually limited. Funding: This clinical trial was funded through University Hospitals Seidman Cancer Center and Washington University School of Medicine Institutional Funds. Correlative analyses were funded in part by the European Union–Next Generation EU–NRRP M6C2–Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (project #PNRR-MAD-2022-12376059), and the Italian Ministry of Health Ricerca Finalizzata 2019 (project #RF-2019-12370243).http://www.sciencedirect.com/science/article/pii/S2589537025000707LymphomaChimeric antigen receptor T cellPoint-of-care manufactureImmune effector cell therapyPhase I |
| spellingShingle | Armin Ghobadi Paolo F. Caimi Jane S. Reese Krishna Goparaju Martina di Trani Julie Ritchey Zachary Jackson Benjamin Tomlinson Jennifer M. Schiavone Sarah Kleinsorge-Block Kayla Zamborsky Linda Eissenberg Dina Schneider Kirsten M. Boughan Emily C. Zabor Leland Metheny Molly Gallogly Winfried Kruger Michael Kadan Andrew Worden A.S Ashish Sharma Brenda W. Cooper Folashade Otegbeye Rafick P. Sekaly David N. Wald Carmelo Carlo-Stella John DiPersio Rimas Orentas Boro Dropulic Marcos de Lima Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context EClinicalMedicine Lymphoma Chimeric antigen receptor T cell Point-of-care manufacture Immune effector cell therapy Phase I |
| title | Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context |
| title_full | Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context |
| title_fullStr | Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context |
| title_full_unstemmed | Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context |
| title_short | Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trialResearch in context |
| title_sort | treatment of non hodgkin lymphoma with point of care manufactured car t cells a dual institution phase 1 trialresearch in context |
| topic | Lymphoma Chimeric antigen receptor T cell Point-of-care manufacture Immune effector cell therapy Phase I |
| url | http://www.sciencedirect.com/science/article/pii/S2589537025000707 |
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