Blockade of TGF-β and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses.

Autor: Kment J; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada.; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada., Newsted D; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada.; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada., Young S; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada., Vermeulen MC; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada., Laight BJ; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada.; Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada., Greer PA; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada.; Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada., Lan Y; EMD Serono Research & Development Institute, Inc., Billerica, MA, USA., Craig AW; Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, ON, Canada. andrew.craig@queensu.ca.; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. andrew.craig@queensu.ca.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2024 Jun; Vol. 130 (12), pp. 2003-2015. Date of Electronic Publication: 2024 Apr 15.
DOI: 10.1038/s41416-024-02677-9
Abstrakt: Background: Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-β (TGF-β) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-β and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models.
Methods: BA is a first-in-class bifunctional inhibitor of TGF-β and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models.
Results: Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-β and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls.
Conclusions: Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.
(© 2024. The Author(s).)
Databáze: MEDLINE
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