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  4. VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding.
 
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Titre

VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding.

Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Journal for ImmunoTherapy of Cancer  
Auteur(s)
Lanitis, E.
Auteure/Auteur
Kosti, P.
Auteure/Auteur
Ronet, C.
Auteure/Auteur
Cribioli, E.
Auteure/Auteur
Rota, G.
Auteure/Auteur
Spill, A.
Auteure/Auteur
Reichenbach, P.
Auteure/Auteur
Zoete, V.
Auteure/Auteur
Dangaj Laniti, D.
Auteure/Auteur
Coukos, G.
Auteure/Auteur
Irving, M.
Auteure/Auteur
Liens vers les personnes
Ronet, Catherine  
Zoete, Vincent  
Rota, Giorgia  
Coukos, George  
Irving, Melita  
Reichenbach, Patrick  
Lanitis, Evripidis  
Dangaj Lanitis, Denarda  
Cribioli, Elisabetta  
Spill, Aodrenn  
Kosti, Paraskevas  
Liens vers les unités
Ludwig Lausanne Branch (LLB)  
Institut Suisse de Bioinformatique  
Recherche en oncologie  
ISSN
2051-1426
Statut éditorial
Publié
Date de publication
2021-08
Volume
9
Numéro
8
Première page
e002151
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The adoptive transfer of chimeric antigen receptor (CAR)-T cells has emerged as a potent immunotherapy against some hematological malignancies but not yet for epithelial-derived solid tumors. One critical issue is the paucity of broadly expressed solid tumor antigens (TAs), and another is the presence of suppressive mechanisms in the tumor microenvironment (TME) that can impair CAR-T cell homing, extravasation and effector functions. TAs expressed by endothelial cells of the tumor vasculature are of clinical interest for CAR therapy because of their genomic stability and accessibility to circulating T cells, as well as their expression across multiple tumor types. In this study, we sought to explore limitations to the efficacy of second-generation (2G) murine CAR-T cells redirected against the vascular endothelial growth factor receptor-2 (VEGFR-2) with the well-characterized single-chain variable fragment DC101.
Primary murine T cells were retrovirally transduced to express a 2G anti-VEGFR-2-CAR, and the in vitro binding to VEGFR-2, as well as reactivity against TA-expressing cells, was evaluated in the absence versus presence of exogenous VEGF-A. The CAR-T cells were further tested in vivo for tumor control alone and in combination with anti-VEGF-A antibody. Finally, we performed ex vivo phenotypic analyses of tumor-infiltrating CAR-T cells for the two treatment groups.
In line with previous reports, we observed poor control of B16 melanoma by the 2G anti-VEGFR-2 CAR-T cells as a monotherapy. We further showed that VEGFR-2 is not downregulated by B16 melanoma tumors post treatment, but that its soluble ligand VEGF-A is upregulated and furthermore competes in vitro with the CAR-T cells for binding to VEGFR-2. This competition resulted in impaired CAR-T cell adhesion and effector function in vitro that could be restored in the presence of anti-VEGF-A antibody. Finally, we demonstrated that coadministration of anti-VEGF-A antibody in vivo promoted CAR-T cell persistence and tumor control and was associated with reduced frequencies of PD-1 <sup>+</sup> Ki67 <sup>-</sup> and LAG-3 <sup>+</sup> Ki67 <sup>-</sup> CAR-T cells in the TME.
This study represents the first example of impaired function of a vasculature-targeted CAR by an angiogenic ligand and rationalizes the use of combinatorial therapies that target the tumor vasculature and augment CAR-T cell effector function.
Sujets

Animals

Humans

Mice

Neoplasms/immunology

Receptors, Chimeric A...

Vascular Endothelial ...

Vascular Endothelial ...

T-lymphocytes

adoptive

antigens

cell engineering

chimeric antigen

immunotherapy

receptors

PID Serval
serval:BIB_3B098C62EF15
DOI
10.1136/jitc-2020-002151
PMID
34389616
Permalien
https://iris.unil.ch/handle/iris/91426
Open Access
Oui
Date de création
2021-12-10T18:49:04.675Z
Date de création dans IRIS
2025-05-20T17:56:06Z
Fichier(s)
En cours de chargement...
Vignette d'image
Nom

34389616_BIB_3B098C62EF15.pdf

Version du manuscrit

preprint

Licence

https://creativecommons.org/licenses/by-nc/4.0

Taille

2.98 MB

Format

Adobe PDF

PID Serval

serval:BIB_3B098C62EF15.P001

Somme de contrôle

(MD5):aa950263be5b321d79af9a69d5c0a2ea

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