Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors
Borazanci, Erkut H. (HonorHealth (Scottsdale, Estats Units d'Amèrica))
Schram, Alison (Memorial Sloan Kettering Cancer Center)
Garralda, Elena (Vall d'Hebron Institut d'Oncologia)
Braña, Irene (Vall d'Hebron Institut d'Oncologia)
Vieito, María (Vall d'Hebron Institut d'Oncologia)
Spreafico, Anna (Princess Margaret Cancer Centre (Toronto, Canadà))
Oliva, Marc (Princess Margaret Cancer Centre (Toronto, Canadà))
Lakhani, Nehal J. (START Midwest (Grand Rapids, Estats Units d'Amèrica))
Hoffman, K. (Northern Biologics (Toronto Canadà))
Hallett, Robin M. (Northern Biologics (Toronto, Canadà))
Maetzel, Dorothea (Northern Biologics (Toronto, Canadà))
Hua, Fei (Applied BioMath (Concord, Estats Units d'Amèrica))
Hilbert, J. (Applied BioMath (Concord, Estats Units d'Amèrica))
Giblin, Patricia (Northern Biologics (Toronto, Canadà))
Anido, Judit (Northern Biologics (Toronto, Canadà))
Kelly, A. (Northern Biologics (Toronto, Canadà))
Vickers, P.J. (Northern Biologics (Toronto, Canadà))
Wasserman, Robert (Northern Biologics (Toronto, Canadà))
Seoane Suárez, Joan (Vall d'Hebron Institut d'Oncologia)
Siu, Lillian L. (Princess Margaret Cancer Centre (Toronto, Canadà))
Hyman, David M. (Memorial Sloan Kettering Cancer Center)
Von Hof, Daniel (HonorHealth, (Scottsdale, Estats Units d'Amèrica))
Tabernero, Josep (Vall d'Hebron Institut d'Oncologia)

Data:	2022
Resum:	Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors. Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1. 1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers. Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23. 7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5. 9 weeks; 23. 7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action. MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Leukemia inhibitory factor ; Monoclonal antibody ; Solid tumors ; STAT3 ; Safety
Publicat a:	ESMO open, Vol. 7 (july 2022) , ISSN 2059-7029

DOI: 10.1016/j.esmoop.2022.100530
PMID: 35921760

11 p, 781.5 KB

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