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

Details

Serval ID
serval:BIB_3B098C62EF15
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding.
Journal
Journal for immunotherapy of cancer
Author(s)
Lanitis E., Kosti P., Ronet C., Cribioli E., Rota G., Spill A., Reichenbach P., Zoete V., Dangaj Laniti D., Coukos G., Irving M.
ISSN
2051-1426 (Electronic)
ISSN-L
2051-1426
Publication state
Published
Issued date
08/2021
Peer-reviewed
Oui
Volume
9
Number
8
Pages
e002151
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
Animals, Humans, Mice, Neoplasms/immunology, Receptors, Chimeric Antigen/genetics, Vascular Endothelial Growth Factor A/metabolism, Vascular Endothelial Growth Factor Receptor-2/metabolism, T-lymphocytes, adoptive, antigens, cell engineering, chimeric antigen, immunotherapy, receptors
Pubmed
Open Access
Yes
Create date
10/12/2021 20:49
Last modification date
17/02/2022 7:33
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