PMID- 38444429 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240307 IS - 2589-5370 (Electronic) IS - 2589-5370 (Linking) VI - 70 DP - 2024 Apr TI - CD19-CAR-DNT cells (RJMty19) in patients with relapsed or refractory large B-cell lymphoma: a phase 1, first-in-human study. PG - 102516 LID - 10.1016/j.eclinm.2024.102516 [doi] LID - 102516 AB - BACKGROUND: Current approved chimeric antigen receptor (CAR) T-cell products are autologous cell therapies that are costly and poorly accessible to patients. We aimed to evaluate the safety and antitumor activity of a novel off-the-shelf anti-CD19 CAR-engineered allogeneic double-negative T cells (RJMty19) in patients with relapsed/refractory large B-cell lymphoma. We report the results from a first-in-human, open-label, single-dose, phase 1 study of allogeneic CD19-specific CAR double-negative T (CAR-DNT) cells. METHODS: Eligibility criteria included the presence of measurable lesions, at least 2 lines of prior immunochemotherapy, and an ECOG score of 0-1. We evaluated four dose levels (DL) of RJMty19 in a 3 + 3 dose-escalation scheme: 1 x 10(6), 3 x 10(6), 9 x 10(6) and 2 x 10(7) CAR-DNT cells per kilogram of body weight. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The primary endpoints were dose-limiting toxicities (DLTs), incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of standard cellular pharmacokinetic parameters, immunogenicity, objective response rates (ORR), and disease control rate (DCR) per Lugano 2014 criteria. FINDINGS: A total of 12 patients were enrolled between 22 July 2022 and 27 July 2023. Among these patients, 66% were classified as stage IV, 75% had an IPI score of 3 or higher, representing an intermediate risk or worse. The maximum tolerated dose was not reached because no DLT was observed. Four patient experienced grade 1 or 2 cytokine release syndrome and dizziness. The most common AEs were hematologic toxicities, including neutropenia (N = 12, 100%), leukopenia (N = 12, 100%), lymphopenia (N = 10, 83%), thrombocytopenia (N = 6, 50%), febrile neutropenia (N = 3, 25%), and anemia (N = 3, 25%). Seven subjects died till the cut-off date, five of them died of disease progression and two of them died of COVID 19. In all patients (N = 12), the ORR was 25% and CRR was 8.3%. DL1 and DL2 patients benefited less from the therapy (ORR: 17%, N = 1; DCR: 33%, N = 2). However, all DL3 patients achieved disease control (N = 3, 100%), and all DL4 patients achieved objective response (N = 3, 100%). INTERPRETATION: Our results demonstrate that CD19-CAR-DNT cells appear to be well tolerated with promising antitumor activity in LBCL patients. Further study of this product with a larger sample size is warranted. This phase 1 study is registered on clinicaltrials.gov (NCT05453669). FUNDING: Wyze Biotech. Co., Ltd. CI - (c) 2024 The Author(s). FAU - Xiao, Xibin AU - Xiao X AD - Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Liu, Hui AU - Liu H AD - Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Qiu, Xi AU - Qiu X AD - Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Chen, Panpan AU - Chen P AD - Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Li, Xian AU - Li X AD - Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Wang, Dan AU - Wang D AD - Wyze Biotech Co., Ltd, Zhongshan, Guangdong, China. FAU - Song, Guangrong AU - Song G AD - Wyze Biotech Co., Ltd, Zhongshan, Guangdong, China. FAU - Cheng, Yu AU - Cheng Y AD - Wyze Biotech Co., Ltd, Zhongshan, Guangdong, China. FAU - Yang, Liming AU - Yang L AD - Wyze Biotech Co., Ltd, Zhongshan, Guangdong, China. FAU - Qian, Wenbin AU - Qian W AD - Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. LA - eng SI - ClinicalTrials.gov/NCT05453669 PT - Journal Article DEP - 20240229 PL - England TA - EClinicalMedicine JT - EClinicalMedicine JID - 101733727 PMC - PMC10912040 OTO - NOTNLM OT - Antitumor activity OT - B-cell lymphoma OT - CD19-CAR-DNT cells OT - Double-negative T cells OT - Safety COIS- DW, GS, YC and LY are employed by Wyze Biotech Co., Ltd, Zhongshan, Guangdong, China. DW and LY are inventors of several DNT cell technology-related patents and intellectual properties. HL, XQ, PC, XL, WQ declare no competing interests. EDAT- 2024/03/06 06:44 MHDA- 2024/03/06 06:45 PMCR- 2024/02/29 CRDT- 2024/03/06 03:47 PHST- 2023/12/14 00:00 [received] PHST- 2024/02/04 00:00 [revised] PHST- 2024/02/16 00:00 [accepted] PHST- 2024/03/06 06:45 [medline] PHST- 2024/03/06 06:44 [pubmed] PHST- 2024/03/06 03:47 [entrez] PHST- 2024/02/29 00:00 [pmc-release] AID - S2589-5370(24)00095-6 [pii] AID - 102516 [pii] AID - 10.1016/j.eclinm.2024.102516 [doi] PST - epublish SO - EClinicalMedicine. 2024 Feb 29;70:102516. doi: 10.1016/j.eclinm.2024.102516. eCollection 2024 Apr.