Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression.

Details

Serval ID
serval:BIB_75DE24FE756B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression.
Journal
The Journal of experimental medicine
Author(s)
Lanitis E., Rota G., Kosti P., Ronet C., Spill A., Seijo B., Romero P., Dangaj D., Coukos G., Irving M.
ISSN
1540-9538 (Electronic)
ISSN-L
0022-1007
Publication state
Published
Issued date
01/02/2021
Peer-reviewed
Oui
Volume
218
Number
2
Pages
e20192203
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Limited clinical benefit has been demonstrated for chimeric antigen receptor (CAR) therapy of solid tumors, but coengineering strategies to generate so-called fourth-generation (4G) CAR-T cells are advancing toward overcoming barriers in the tumor microenvironment (TME) for improved responses. In large part due to technical challenges, there are relatively few preclinical CAR therapy studies in immunocompetent, syngeneic tumor-bearing mice. Here, we describe optimized methods for the efficient retroviral transduction and expansion of murine T lymphocytes of a predominantly central memory T cell (TCM cell) phenotype. We present a bicistronic retroviral vector encoding both a tumor vasculature-targeted CAR and murine interleukin-15 (mIL-15), conferring enhanced effector functions, engraftment, tumor control, and TME reprogramming, including NK cell activation and reduced presence of M2 macrophages. The 4G-CAR-T cells coexpressing mIL-15 were further characterized by up-regulation of the antiapoptotic marker Bcl-2 and lower cell-surface expression of the inhibitory receptor PD-1. Overall, this work introduces robust tools for the development and evaluation of 4G-CAR-T cells in immunocompetent mice, an important step toward the acceleration of effective therapies reaching the clinic.
Pubmed
Open Access
Yes
Create date
22/11/2020 11:39
Last modification date
28/11/2020 6:26
Usage data