Synapse - Results from first-in-human phase I study of a novel CD19-1XX chimeric antigen receptor with calibrated signaling in Large B-cell lymphoma

Results from first-in-human phase I study of a novel CD19-1XX chimeric antigen receptor with calibrated signaling in Large B-cell lymphoma Journal Article

Authors:	Park, J. H.; Palomba, M. L.; Perica, K.; Devlin, S. M.; Shah, G.; Dahi, P. B.; Lin, R. J.; Salles, G.; Scordo, M.; Nath, K.; Valtis, Y. K.; Lynch, A.; Cathcart, E.; Zhang, H.; Schoder, H.; Leithner, D.; Liotta, K.; Yu, A.; Stocker, K.; Li, J.; Dey, A.; Sellner, L.; Singh, R.; Sundaresan, V.; Tong, X.; Zhao, F.; Mansilla-Soto, J.; He, C.; Meyerson, J.; Hosszu, K.; McAvoy, D.; Wang, X.; Rivière, I.; Sadelain, M.
Article Title:	Results from first-in-human phase I study of a novel CD19-1XX chimeric antigen receptor with calibrated signaling in Large B-cell lymphoma
Abstract:	PURPOSEWe designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3 zeta and 4-1BB/CD3 zeta CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities.METHODSIn this first-in-human, phase I, dose escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma received 19(T2)28z-1XX CAR T cells at four dose levels (DLs), ranging from 25 to 200 x 106.RESULTSTwenty-eight patients underwent apheresis and received CAR T cells. Sixteen and 12 patients were treated in the dose escalation and expansion cohorts, respectively. The overall response rate (ORR) was 82% and complete response (CR) rate was 71% in the entire cohort. The lowest dose of 25 x 106 was selected for dose expansion. In 16 patients treated at this DL, 88% achieved ORR and 75% CR. With the median follow-up of 24 months, the 1-year event-free survival was 61% (95% CI, 45 to 82) and 14 patients remain in continuous CR beyond 12 months. In all cohorts, grade >= 3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome rates were low at 4% and 7%, respectively. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory features, and CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission.CONCLUSIONThe calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.
Keywords:	chemotherapy; neurotoxicity; therapy; multicenter; lisocabtagene maraleucel
Journal Title:	Journal of Clinical Oncology
Volume:	43
Issue:	21
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2025-07-20
Start Page:	2418
End Page:	2428
Language:	English
ACCESSION:	WOS:001525182500001
DOI:	10.1200/jco-24-02424
PROVIDER:	wos
PMCID:	PMC12270773
PUBMED:	39883889
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Jae H. Park -- Source: Wos