EClinicalMedicine · 2025
Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trial.
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Ghobadi Armin, Caimi Paolo F, Reese Jane S, Goparaju Krishna, di Trani Martina, Ritchey Julie, Jackson Zachary, Tomlinson Benjamin, Schiavone Jennifer M, Kleinsorge-Block Sarah, Zamborsky Kayla, Eissenberg Linda, Schneider Dina, Boughan Kirsten M, Zabor Emily C, Metheny Leland, Gallogly Molly, Kruger Winfried, Kadan Michael, Worden A S Andrew, Sharma Ashish, Cooper Brenda W, Otegbeye Folashade, Sekaly Rafick P, Wald David N, Carlo-Stella Carmelo, DiPersio John, Orentas Rimas, Dropulic Boro, de Lima Marcos
Аннотация
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.govNCT03434769.
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).
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.govNCT03434769.
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).